Substituted oxotremorine derivatives

ABSTRACT

This disclosure describes novel substituted oxotremorine derivatives of formula I having nitrogen, oxygen or sulfur groups and the prodrug forms of these derivatives. The compounds have cholinergic activity. Also disclosed are methods for treating diseases of the central nervous system in mammals employing the compounds, pharmaceutical preparations containing the compounds and the processes for the production of the compounds. ##STR1##

CONTROL REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 08/392,436 filed Feb. 22, 1995, now U.S. Pat. No. 5,550,257 which is a CIP of application Ser. No. 274,604 filed Jul. 13, 1994, now U.S. Pat. No. 5,451,685 which is a divisional of 07/690,749 filed Apr. 24, 1991, now U.S. Pat. No. 5,356,885.

BACKGROUND OF INVENTION

The invention relates to compounds, pharmaceutical compositions and to the use of the compounds for the manufacture of pharmaceuticals.

A chronic deficiency in central cholinergic function has been implicated in a variety of neurologic and psychiatric disorders, including senile dementia of the Alzheimer's type (SDAT), tardive dyskinesia, Pick's disease and Huntington's chorea. Postmortem neurochemical investigations of patients with SDAT have demonstrated a reduction in presynaptic markers for acetylcholine utilizing neurons in the hippocampus and the cerebral cortex [P. Davies and A. J. R. Maloney, Lancet, 1976, 1403, (1976); E. K. Perry, R. H. Perry, G. Blessed, B. E. Tomlinson, J. Neurol. Sci., 34, 247, (1976)]. The basis for the cholinergic abnormality is unclear, but evidence suggests that the cholingergic neurons in the nucleus basalis of Meynert may selectively degenerate in SDAT [J. T. Coyle, D. J. Price, M. R. DeLong, Science, 219, 1184, (1983)]. If this degeneration plays a role in behavior symptoms of the disease, then a possible treatment strategy would be to compensate for the loss of cholinergic output to the cortex and hippocampus.

In an aged monkey animal model, designed to mimic the symptoms of SDAT, the direct muscarinic agonists arecoline [R. T. Bartus, R. L. Dean, B. Beer, Neurobiology of Aging, 1, 145, (1980)] and oxotremorine [R. T. Bartus, R. L. Dean, B. Beer, Psychopharmacology Bulletin, 19, 168, (1983)] produced significant improvement in performance. These results in aged monkeys were corroborated in SDAT patients with arecoline which produced a more consistent improvement when compared to the anticholinergic inhibitor physostigmine [J. E. Christie, A. Shering, J. Ferguson, A. M. Glen, British Journal of Psychiatry, 138, 46, (1981)].

These animal behavioral and clinical results have instigated significant efforts in a search for a muscarinic agonist which will selectively compensate for the loss of cholinergic input in the hippocampus and cerebral cortex. However, the search must be refined to seek agonists which will not affect significantly the remaining body cholinergic functions. The recent disclosure that muscarinic receptors are not all the same but exist as a heterogeneous population of receptors substantiates the possibility for the discovery of a selective muscarinic agonist [T. I. Bonner, N. J. Buckley, A. C. Young, M. R. Brann, Science, 237, 527, (1987)].

The methodical methylation of the muscarinic agonist oxotremorine and its derivatives has been studied in the search for a selective muscarinic agonist [B. Ringdahl, J. Med. Chem., 31, 683, (1988); B. Ringdahl, "Structural Determinants of Muscarinic Agonist Activity" The Muscarinic Receptors, J. H. Brown Ed., The Humana Press, Clifton, N.J., 1989, 151]. The methodical substitution of a methyl group onto oxotremorine can probe the steric non-polar environment of the muscarinic agonist for its neurotransmitter-receptor-complex.

The present invention describes the preparations. of oxotremorine derivatives having polar substituted oxygen and substituted sulfur groups. This series of compounds goes beyond the initial study by Ringdall. In addition to exploring the steric environment of the muscarinic agonist for its neurotransmitter complex, the compounds of the present invention probe possible auxiliary polar interactions with one of the muscarinic receptors.

SUMMARY OF THE INVENTION

This invention is concerned with new compounds of formula I which have cholinergic activity; with methods of treating diseases of the central nervous system in meals employing these new compound; with pharmaceutical preparations containing these compound; and with processes for the production of these compounds. ##STR2## wherein R₁ and R₂ are each independently selected from the group consisting of (C₁ -C₆)alkyl and (C₃ -C₇ )cycloalkyl; or one of R₁ and R₂ is (C₁ -C₆)alkyl and the other is --(CH₂)_(n) R₁₇, and n is 2 to 6; or

R₁ and R₂ when taken together with the associated N(itrogen) atom is imidazole or may form a moiety of formula II: ##STR3## A is carbon, nitrogen, oxygen or sulfur; m is 0, 1 or 2;

R₉, R₁₀ are hydrogen; hydroxymethyl;

(C₁ -C₆)trialkylsilyloxymethyl, halomethyl, wherein halo is Cl, Br, I; or alkyl- aryl- or substituted arylsulfonylmethyl; with the proviso that when m is 0 or 1, and

R₇, R₈, R₉, R₁₀ are other than hydrogen, A is carbon;

wherein

R₃, R₄, R₅, R₆, R₇, R₈, R₁₇ are selected from hydrogen, amino, substituted amino, mono(C₁ -C₆)alkylamino, substituted mono(C₁ -C₆)alkylamino, di(C₁ -C₆)alkylamino, azido, hydroxy, substituted hydroxy, (C₁ -C₆)alkoxyl, (C₁ -C₆)alkyloxymethyleneoxy, aryl(C₁ -C₄)alkyloxymethyleneoxy, substituted aryl(C₁ -C₄)alkyloxymethyleneoxy, (C₁ -C₁₀)acyloxymethyleneoxy, aroyloxymethyleneoxy, substituted aroyloxymethyleneoxy, thio, substituted thio, (C₁ -C₆)alkylthio, (C₁ -C₆)alkyldithio, and (C₁ -C₆)trialkylsilyloxy;

wherein

the aforesaid substituted amino or substituted mono(C₁ -C₆)alkylamino moieties may be substituted with a carbonyl moiety selected from (C₁ -C₁₀)acyl, (C₃ -C₇)cycloalkylcarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]carbonyl, heterocycloalkylcarbonyl, aroyl, aryl(C₁ -C₄)alkyl-carbonyl, heteroaroyl, heteroaryl(C₁ -C₄)alkylcarbonyl, (C₁ -C₁₀)alkoxycarbonyl, (C₃ -C₇)cycloalkoxycarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkoxy]carbonyl, heterocycloalkoxycarbonyl, heterocycloalkyl[C₁ -C₄)alkoxy]carbonyl, aryloxycarbonyl, aryl(C₁ -C₄)alkoxycarbonyl, and heteroaryl(C₁ -C₄)alkoxycarbonyl;

wherein

the aforesaid substituted hydroxy moieties may be substituted with a carbonyl moiety selected from (C₁ -C₁₀)acyl, (C₃ -C₇)cycloalkylcarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]carbonyl, heterocycloalkylcarbonyl, aroyl, aryl(C₁ -C₄)alkylcarbonyl, heteroaroyl, substituted heteroaroyl, heteroaryl (C₁ -C₄)alkylcarbonyl, (C₁ -C₁₀)alkoxycarbonyl, (C₃ -C₇)cycloalkoxycarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkoxy]carbonyl, heterocycloalkyloxycarbonyl, heterocycloalkyl[(C₁ -C₄)alkoxy]carbonyl, aryloxycarbonyl, aryl(C₁ -C₄)alkyloxycarbonyl, heteroaryl(C₁ -C₄)alkoxycarbonyl, (C₁ -C₁₀)alkylaminocarbonyl, (C₃ -C₇)cycloalkylaminocarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]aminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, aryl(C₁ -C₄)alkylaminocarbonyl, heteroarlyaminocarbonyl, heteroaryl(C₁ -C₄)alkylaminocarbonyl, (C₁ -C₁₀)dialkylaminocarbonyl, aryl[(C₁ -C₄)alkyl]aminocarbonyl, (C₃ -C₇)cycloalkylalkylaminocarbonyl, diarylaminocarbonyl, and bis[aryl(C₁ -C₄)alkyl]aminocarbonyl;

wherein

the aforesaid substituted thio moiety may be substituted with a carbonyl moiety selected from (C₁ -C₁₀)acyl, (C₃ -C₇)cycloalkylcarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]carbonyl, heterocycloalkylcarbonyl, aroyl, aryl(C₁ -C₄)alkylcarbonyl, heteroarylcarbonyl, heteroaryl (C₁ -C₄)alkylcarbonyl, (C₁ -C₁₀)alkoxycarbonyl, (C₃ -C₇)cycloalkoxycarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkoxy]carbonyl, heterocycloalkyloxycarbonyl, heterocycloalkyl[(C₁ -C₄)alkoxy]carbonyl, aryloxycarbonyl, aryl(C₁ -C₄)alkyloxycarbonyl, heteroaryl(C₁ -C₄)alkoxycarbonyl, (C₁ -C₁₀)alkylaminocarbonyl, (C₃ -C₇)cycloalkylaminocarbonyl, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]aminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, aryl(C₁ -C₄)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C₁ -C₄)alkylaminocarbonyl, (C₁ -C₁₀)dialkylaminocarbonyl, aryl[(C₁ -C₄)alkyl]aminocarbonyl, (C₄ -C₇)cycloalkylalkylaminocarbonyl, diarylaminocarbonyl, and bis[aryl(C₁ -C₄)alkyl]aminocarbonyl;

wherein

either R₃ or R₄ may also be selected from (C₁ -C₆)alkyl with the proviso that:

the other must be selected from hydrogen, hydroxy, substituted hydroxy;

R₅ and R₆ must be hydrogen;

R₁ and R₂ independently may not be (C₁ -C₆)alkyl, (C₃ -C₇)cycloalkyl; or

R₁ and R₂ taken together with the associated N(itrogen) atom may not be azetidine, pyrrolidine or piperidine;

with the proviso that:

if there is a substituent at R₇, R₈, R₉ or R₁₀ then the other of these substituents must be hydrogen;

A must be carbon; and

m must be 1;

with the proviso that:

if there is a hydroxy, substituted hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkyloxymethyleneoxy, aryl(C₁ -C₄)alkyloxymethyleneoxy, substituted aryl(C₁ -C₄)alkyloxymethyleneoxy, (C₁ -C₁₀)acyloxymethyleneoxy, aroyloxymethyleneoxy, substituted aroyloxymethyleneoxy or (C₁ -C₆) trialkylsilyloxy substituent at R₃ or R₄ ;

the other substituent must be either hydrogen or (C₁ -C₆)alkyl;

and R₅ and R₆ must be hydrogen; or if there is an amino, substituted amino, mono(C₁ -C₆)alkylamino, substituted mono(C₁ -C₆)alkylamino, di(C₁ -C₆)alkylanino, azido, thio, substituted thio, (C₁ -C₆)alkylthio, or (C₁ -C₆)alkyldithio substituent at R₃ or R₄ ;

the other substituent must be hydrogen;

with the proviso that:

if there is a substituent other than hydrogen at R₅ or R₆ then the other substituent must be hydrogen;

R₃ and R₄ are hydrogen; and

R₁ and R₂ must be independently selected from the group consisting of straight or branched chain (C₁ -C₆)alkyl and (C₃ -C₇)cycloalkyl; or

R₁ and R₂ when taken together with the associated N(itrogen) atom is imidazole or may form a moiety as in formula II: ##STR4## wherein R₇, R₈, R₉ and R₁₀ must be hydrogen;

A must be carbon; and

m must be 0, 1.

with the proviso that:

if R₃, R₄, R₅ and R₆ are all hydrogen then R₁ and R₂ when taken together with the associated N(itrogen) atom is imidazole or may form a moiety as in formula II: ##STR5## wherein R₇ and R₈ are as above defined but must not both be hydrogen;

R₉ and R₁₀ must be hydrogen;

A must be carbon; and

m must be 1;

and the pharmaceutically acceptable salts.

DESCRIPTION OF THE INVENTION

In the compounds of the invention, the groups and atoms are defined below:

(C₁ -C₆)alkyl group represent one to six carbon atoms either in a straight chain such as ethyl, n-butyl, n-hexyl or are branched such as tert-butyl, 3-methylpentyl.

(C₁ -C₄)alkyl group represent one to four carbon atoms in a straight chain such as methylene, ethylene, propylene, butylene and are used to tether a cycloalky, aryl, heterocycloalkyl or hereroaryl group to the carbonyl moiety.

(C₁ -C₁₀)acyl group represent an alphatic part which may be straight or branched chain saturated or may have carbon carbon unsaturation attached to a carbonyl functionality and is exemplified by formyl, acetyl, propionyl, crotonyl, acryloyl groups.

(C₁ -C₁₀)alkoxy group represents an alphatic part which may be straight or branched chain, or may have carbon carbon unsaturation and is attached to an oxygen atom and is exemplified by methoxy and isobutoxy, sec-butoxy, isopropoxy, hexyloxy of which the (C₁ -C₄)alkoxy group are preferred.

(C₃ -C₇)cycloalkyl group represents groups such as cyclopropyl, cyclopentyl, and cyclohexyl and these groups can be attached directly to a carbonyl moiety such as cycolpentylcarbonyl or to an intervening oxygen or nitrogen atom such as cyclohexyloxycarbonyl and cyclopentylaminocarbonyl respectively.

(C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl represents a three to seven carbon ring attached to a one to four carbon straight alkyl chain and is exemplified by cyclopropylmethyl, cyclohexylethyl and cyclobutylpropyl.

Heterocycloalkyl group represents a heterocyclic group having from four to eight ring atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms with the remainder being carbon atoms. In the heterocyclic groups, the atom through which the heterocyclic is attached is preferably a carbon atom. Examples of such heterocyclic ring systems include tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-piperidinyl, 2-morpholinyl.

Aryl group represents an aromatic group such as phenyl, 2-naphthyl, 4-biphenyl.

Heteroaryl group represents a heteroaromatic group having one or two rings with from five to ten ring atoms, of which one to four are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms with the remainder being carbon atoms. In the heterocyclic groups the atom through which the heterocyclic is attached is preferably a carbon atom. Examples of such heteroaryl ring systems include pyrrolyl, thieyl, furyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, quinolyl.

The aryl and heteroaryl ring systems may be unsubstituted or substituted on the carbon atoms of the aryl or heteroaryl groups. Substituents include (C₁ -C₆)alkyl, alkoxy, methylthio, dialkylamino, alkoxycarbonyl, dialkylaminocarbonyl, cyano, nitro, trifluoromethyl or halo selected from fluoro, chloro, bromo and iodo.

The novel compounds of the present invention may be readily prepared in accordance with one or more of the following reaction schemes wherein R₁ ' and R₂ ' are selected from (C₁ -C₆)alkyl or one of R₁ ' and R₂ ' is (C₁ -C₆)alkyl and the other is --(CH₂)_(n) R₁₇ ' where n is 2-6; or R₁ ' and R₂ ' when taken together with the associated N(itrogen) form a moiety of formula II: ##STR6## where A' is C, N, O; m is 0, 1, or 2;

R₉ ' and R₁₀ ' are selected from hydrogen, hydroxymethyl and (C₁ -C₆)trialkylsilyloxymethyl, with the proviso that when m is 0 or 1 and one of the R₇ ', R₈ ', R₉ ' and R₁₀ ' is other than hydrogen, the other substituents are hydrogen and A' is carbon;

R₃ ', R₄ ', R₅ ', R₆ ', R₇ ', R₈ ', and R₁₇ ' are independently selected from hydrogen, hydroxy, substituted hydroxy, (C₁ -C₆)alkoxy and (C₁ -C₆)trialkylsilyloxy R₃ ' or R₄ ' may also be selected from (C₁ -C₆)alkyl; with the proviso that if there is a substituent other than hydrogen at R₅ ' or R₆ ' the other substitutent must be hydrogen and R₃ ' and R₄ ' are hydrogen; with the proviso that only one of R₃ ' or R₄ ' is (C₁ -C₆)alkyl, hydroxy, substituted hydroxy, (C₁ -C₆)alkoxy or (C₁ -C₆)trialkylsilyloxy; R₁₁ is isopropyl when R₁₂ is hydrogen or R₁₁ is phenyl when R₁₂ is methyl; R₁₃ and R₁₄ are selected from hydrogen and (C₁ -C₆)alkyl; R₁₅ is hydrogen or (C₁ -C₆)alkyl; R₁₆ is hydrogen or (C₁ -C₆)alkyl; P is (C₁ -C₆)alkyl, aryl(C₁ -C₄)alkyl, substituted cycloalkyl or substituted oxazalone. ##STR7##

SCHEME I

In accordance with Scheme I, the diamines of general formula 4 and 5 are prepared by a modification of previously described methods [U. Swenson, U. Hacksell, R. Dahlboom. Acta Pharm. Suec., (1978), 15, 67; H. Bittiger, J. Heid, U.S. Pat. No. 3,354,178 (1967)]. The advantage, over the published procedures, is the mild conditions used to remove the trifluoroacetamide protecting group.

Propargylamine is treated with trifluoroacetic acid anhydride in a solvent such as diethyl ether, tetrahydrofuran or methylene chloride to afford trifluoroacetamide 2. Compound 2 is reacted with paraformaldehyde, acetic or propanoic acid, cuprous halide and a secondary amine such as pyrrolidine, dimethylamine, piperidine, (R)-3-acetoxypyrroldine or (S)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]methylpyrrolidine in a ethereal solvent such as diethyl ether, tetrahydrofuran or dioxane at the reflux temperature of the solvent to give the amine of general formula 3. A compound of general formula 3 is reacted in an alcohol solvent such as methanol, ethanol or isopropanol containing a mineral acid to produce a diamine of general formula 4. When compounds of general formula 3 contain an acid labile group, such as (S)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]methylpyrrolidine, treatment with sodium borohydride in an alcohol solvent gives diamines of general formula 5. ##STR8##

SCHEME II

In accordance with Scheme II, ester 8, wherein R₁₅ =(C₁ -C₆)alkyl, is prepared by the procedure of J. K. Whitesell et al., J. Org. Chem., 1989,54,2258. Ester 8 wherein R₁₅ =hydrogen is prepared by the procedure of J. K. Whitesell et al., Tetrahedron, 1986, 42,2993.

Phenylcyclohexanone, in the racemic or optically active form (Chima, 1986, 40,318, Organic Synthesis, 1990, Vol 69, 1) is reacted with an α-ketoacid, such as pyruvic acid, in an inert solvent, such as benzene or toluene, in the presence of a catalytic amount of p-toluenesulfonic acid. Water is removed by azeotropic distillation to give a compound of general formula 7 wherein R₁₅ =(C₁ -C₆)alkyl. A compound of formula 7 is reacted with allyltrimethylsilane in the presence of stannic chloride in an inert solvent, such as methylene chloride, at -78° C. to give a compound of general formula 8.

Compounds of general formula 13 are optically active, wherein one of R₁₃ or R₁₄ =(C₁ -C₆)alkyl and the other one is hydrogen, are prepared by the procedure of D. A. Evans et. al., J. Am. Chem. Soc., 1982, 104,1737.

A compound of general formula 9 is reacted with a lower alkyllithium reagent in an ether solvent, such as diethyl ether or tetrahydrofuran, at -78° C. followed by the addition of a (C₂ -C₈)alkylcarboxylic acid chloride to give compounds of general formula 10. Alternatively, a compound of the general formula 9 is reacted with a lower alkyllithium reagent in an ether solvent, such as diethyl ether or tetrahydrofuran, at -78° C. followed by the addition of a 4-pentenoic acid chloride to give compounds of general formula 11. Reacting compounds of general formula 10 with a lower alkyllithium reagent, such as n-butyllithium or t-butyllithium, in an inert solvent, such as diethyl ether or tetrahydrofuran, at -78° C.; followed by the addition of a 2-propenyl halide and warming to -20° C. gives products of general formula 12. Alternately, reacting compounds of general formula 11 with a lower alkyllithium reagent, such as n-butyl-lithium or t-butyllithium, in an inert solvent, such as diethyl ether or tetrahydrofuran, at -78° C.; followed by the addition of a (C₁ -C₆)alkyl halide and warming to -20° C. gives compounds of general formula 12. The addition of compounds of general formula 12 to a solution of a (C₁ -C₆)alkyl alcohol or phenylmethyl alcohol and an alkyllithium reagent in an ether solvent, such as diethyl ether or tetrahydrofuran, at 0° C. gives compounds of general formula 13.

Compounds of general formula 17, wherein R₁₆ =(C₁ -C₆)alkyl and the other is hydrogen, are prepared by the procedure of A. V. Rama Rao et. al., Tetrahedron Letters, 1988, 29, 2069.

The dialkyl ester of (C₁ -C₆)alkyl malonate 14 is treated, with an alkali metal alkoxide and subsequently reacted with a 2-propenyl halide, such as allylbromide, to give the disubstituted malonate ester 15. Ester 15 is subjected to saponification, using potassium hydroxide in a (C₁ -C₆)alkyl alcohol, such as ethyl alcohol; followed by acidification, with a mineral acid; and decarboxylation by distillation to give the racemic acid 16. Reacting compound 15 with thionyl chloride or oxalyl chloride; followed by the addition of a (C₁ -C₆)alkyl alcohol, such as ethyl alcohol, or an arylmethyl alcohol, such as benzyl alcohol, gives the racemic ester 17.

As cited in the reference, the racemic acid may be resolved by reacting the product of treatment with thionyl chloride or oxalyl chloride with a resolving agent, such as L-phenylalaninol.

Compounds 8, 13 and 17 are of general formula 18, where P is as previously described. ##STR9##

SCHEME III

In accordance with Scheme III compounds of general formula 18 prepared in accordance with Scheme II are reacted with compounds of general formulas 4, 5 prepared in accordance with Scheme I to ultimately yield the compounds of the present invention. Accordingly, compound of general formula 18 is treated with a stream of ozone at -78° C. in methylene chloride or a (C₁ -C₆)alcohol, such as methyl alcohol or ethyl alcohol. The resulting solution is treated with a reducing agent, like a thioether, such as dimethylsulfide, a phosphine, such as triphenylphosphine, or zinc and acetic acid, to obtain an aldehyde of the general formula 19. An aldehyde of general formula 19 is reacted with a diamine of general formula 4 or 5 prepared as in Scheme I and sodium cyanoborohydride, in an alcohol solvent, such as methyl alcohol or ethyl alcohol containing a (C₁ -C₆)alkylcarboxylic acid or a strong mineral acid to maintain an acidic pH, to give an aminoester of general formula 20. A compound of general formula 20 is converted to a lactam of general formula 21 by stirring at room temperature or heating at the reflux temperature of the alcohol solvent, such as methyl alcohol or ethyl alcohol, in the presence of an alkalimetal carbonate.

A compound of general formula 21, wherein R₃ ' or R₄ ' is not hydroxyl, is reacted at room temperature with cyanogen bromide in an ether solvent, such as diethyl ether, to give a compound of general formula 22. When a compound of general formula 21 contains a free hydroxyl, (i.e., R₃ ' or R₄ '=hydroxyl), it is necessary to protect the hydroxyl group, for example as a silyl ether, by reacting the free hydroxyl with a trialkylsilyl chloride, such as t-butyldimethylsilyl chloride, and a trialkylamine, such as triethylamine, in an inert solvent, such as methylene chloride, before the compound is treated with cyanogen bromide. A compound of general formula 22 is treated with a secondary amine, such as pyrrolidine, dimethylamine, piperidine, (R)-3-acetoxypyrrolidine, (R)-[[(1,1-dimethylethyl)dimethylsilyl]oxy]pyrrolidine or (S)-2-[[[(1,1-dimethyethyl)dimethylsilyl]oxy]methy]pyrrolidine to give a compound of general formula 23, where the protecting groups are retained. Removal of the silyloxy protecting group is achieved by treatment of the silylether with mineral acid or fluoride ion in an alcohol solvent. A compound of general formula 21 can be converted to a compound of general formula 23 using the procedures described in U.S. Pat. No. 4,937,235 and in Schemes IV-IX of the present invention. ##STR10##

SCHEME IV

In accordance with Scheme IV, the preparation of the compounds of the present invention wherein R₃ or R₄ are amino or azido are described. In the foregoing Scheme IV, Compound 24 is a subset of compound 23, where R₃ ' and R₄ ' are independently selected from hydroxyl or R₁₅, wherein R₁₅ is (C₁ -C₆)alkyl or hydrogen. Where R₁₅ is hydrogen, the compounds may be prepared as in Schemes I-III or as described in U.S. Pat. No. 4,937,235. Where R₁₅ is (C₁ -C₆)alkyl, the compounds may be prepared as in Schemes I-III.

In accordance with Scheme IV, a compound of general formula 24 is reacted with an alkyl or arylsulfonyl chloride in the presence of an amine base such as pyridine or triethylamine; in an ether or a chlorohydrocarbon solvent at 0° C. (∓5° C.), to produce a compound of general formula 25. Treatment of compound 25 with an alkali metal azide, in an alcohol or a polar aprotic solvent such as dimethylformamide, at from room temperature to the reflux temperature of the solvent, gives a compound of general formula 26. Compound 26 is treated with a reducing agent, such as zinc in acetic acid or wet triphenylphosphine, to give a compound of general formula 27. ##STR11##

SCHEME V

In accordance with Scheme V, the preparation of the compounds of the present invention wherein R₅ or R₆ are amino or azido is described. Accordingly, a compound of general formula 28, prepared by the methods described in U.S. Pat. No. 4,937,235, is reacted with an alkyl or arylsulfonyl chloride in the presence of an amine base such as pyridine or triethylamine, in an ether or a chlorohydrocarbon solvent at 0° C. (±5° C.) to produce a compound of general formula 29. Treatment of compound 29 with an alkali metal azide, in an alcohol or a polar aprotic solvent such as dimethylformamide, at from room temperature to the reflux temperature of the solvent, gives a compound of general formula 30. Compound 30 is treated with a reducing agent, such as zinc in acetic acid or wet triphenylphosphine, to give a compound of general formula 31. ##STR12##

SCHEME VI

In accordance with Scheme VI, compound 24, prepared by methods described in U.S. Pat. No. 4,937,235 or as in Schemes I-III, is reacted with a carboxylic acid chloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl (C₁ -C₄)alkyl, heterocycloalkyl, aryl aryl(C₁ -C₄)alkyl, heteroaryl, substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 32.

Compound 24 is reacted with a chloroformate such as a (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 33.

Compound 24 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as (C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl or bis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 34.

Alternatively, compound 35, prepared by the methods described in U.S. Pat. No. 4,937,235 is reacted with a carboxylic acid chloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl, heteroaryl, substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 36.

Compound 35 is reacted with a chloroformate such as a (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 37.

Compound 35 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as (C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl or bis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 38.

Compound 36, 37, and 38 are reacted with paraformaldehyde, acetic, acid, copper(I) or (II) chloride and a secondary amine as disclosed in R₁ ' and R₂ ' such as pyrrolidine, in an ether solvent, such as dioxane, in an inert atmosphere at the reflux temperature of the solvent, to give on basification, the corresponding compound of general formula 32, 33, and 34 wherein R₁ and R₂ are selected from R₁ ' and R₂ '. ##STR13##

SCHEME VII

In accordance with Scheme VII, compound 39, prepared by the methods described in U.S. Pat. No. 4,937,235, is reacted with a carboxylic acid chloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl, heteroaryl, substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 40.

Compound 39 is reacted with a with chloroformate such as a (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, heterocycloalkyl (C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl (C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 41.

Compound 39 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as (C₁ -C₁₀)dialkyl , aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl or bis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 42.

Alternatively, compound 43, prepared by the methods described in U.S. Pat. No. 4,937,235, is reacted with a carboxylic acid chloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl, heteroaryl, substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 44.

Compound 43 is reacted with a chloroformate such as a (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 45.

Compound 43 is reacted with an isocyanate such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as (C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl or bis[aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at 0° C.(±5° C.) to give a compound of general formula 46.

Compound 44, 45 and 46 are reacted with paraformaldehyde, acetic, acid, copper (I) or (II) chloride and a secondary amine as disclosed in R₁ ' and R₂ ' such as pyrrolidine, in an ether solvent, such as dioxane, in an inert atmosphere at the reflux temperature of the solvent, to give on basification, the corresponding compound of general formula 40, 41, and 42 wherein R₁ and R₂ are selected from R₁ ' and R₂ '. ##STR14##

SCHEME VIII

In accordance with Scheme VIII, compounds of general formula 27, prepared in accordance with Scheme IV are reacted with a carboxylic choride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl, heteroaryl, substituted heteroaryl, or heteroayl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at or near 0° C. to give a compound of general formula 47. The compounds of general formula 27 are prepared in accordance with Scheme IV are reacted with a chloroformate such as a (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chorohydrocarbon solvent, at or near 0° C. to give a compound of general formula 48. ##STR15##

SCHEME IX

In accordance with Scheme IX, compound of general formula 49, prepared in accordance with U.S. Pat. No. 4,937,235 are reacted with a carboxylic acid chloride or anhydride such as (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, aryl, aryl(C₁ -C₄)alkyl, heteroaryl; substituted heteroaryl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at or near 0° C. to give a compound of general formula 50. Compounds of general formula 49 are reacted with a chloroformate such as a (C₁ -C₁₀)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkyl, heterocycloalkyl, heterocycloalkyl(C₁ -C₄)alkyl, aryl, aryl(C₁ -C₄)alkyl, or heteroaryl(C₁ -C₄)alkyl in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at or near 0° C. to give a compound of general formula 51. Compound of general formula 49 are reacted with an isocyanate such as (C₁ -C.sub. 10)alkyl, (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkyl (C₁ -C₄)alkyl, heterocycloalkyl, aryl, heteroaryl, or heteroaryl(C₁ -C₄)alkyl; or a carbamyl chloride such as (C₁ -C₁₀)dialkyl, aryl(C₁ -C₄)alkyl, (C₄ -C₇)cycloalkyl, diaryl or bis [aryl(C₁ -C₄)alkyl] in the presence of a base such as pyridine or triethylamine, in an ether or chlorohydrocarbon solvent, at or near 0° C. to give a compound of general formula 52.

The compounds of this invention are tested for cholinergic activity according to the following procedures.

[³ H] Quinuclidinyl Benzilate Binding Assay

This assay is utilized in conjunction with the ³ H-Cis-methyldioxolane binding assay to evaluate antagonist and high affinity agonist binding properties of CNS cholinergic agents. The procedure was adapted from Watson, M., Yamamura, H. I., and Roeske, W. R., J. Pharmacol. Exp. Ther. 237: 411-418 (1986) and Watson, M., Roeske, W. R., and Yamamura, H.I., J. Pharmacol. Exp. Ther. 237: 419-427 (1986).

Tissue Preparation:

Rats are sacrificed by decapitation and the brain removed and placed on ice. The cerebral cortex is dissected on a cold stage, weighed and homogenized (Polytron, setting 5.5 with PT-10 saw-tooth generator for 15 seconds) in 50 volumes (wet wt/vol) of ice-cold 10 mM (8.1 mM Na₂ HPO₄, 1.9 mM KH₂ PO₄) sodium-potassium phosphate buffer (NaKPB), pH 7.4. The homogenate is placed in an ice bath for 30 seconds and homogenized again as above. This procedure is repeated once again for a total of three times. The resulting homogenate is then diluted 1:3000 (original wet wt/vol) with ice-cold NaKPB for use in the assay. The final protein content per 2.0 ml of incubation mixture is 0.1 mg.

Dilution of Compounds:

A stock solution of Atropine is prepared at 0.2 mM to define non-specific binding (1 μM final conc). Test compounds are prepared at 40 mM (final conc 1 mM) in buffer (if water soluble) or in absolute ethanol--1N HCl (1:1, v/v) and serially diluted to the desired concentrations. In general, dose-response profiles are examined between 1 mM and 1 pM final concentrations.

Preparation of ³ H-QNB:

³ H-QNB (NEN, NET-656; specific activity=30.0 Ci/mmol) is diluted to 5 nM, with NaPB (final concentation=0.25 nM activity 18,000 cpm at a counting efficiency of 55%).

³ H-QNB Binding Assay:

A typical protocol is outlined below:

    ______________________________________                                                                      Test                                                                           Com-                                              Tube          Buffer  Atropine                                                                              pound .sup.3 H-QNB                                                                          Tissue                               No.   ID*     μL   μL  μL μL  ml                                   ______________________________________                                         1-2   Total   50      --     --    100    1.85                                 3-4   NS      40      10     --    "      "                                    5-6   4e-11   --      --     50    "      "                                    7-8   4e-10   --      --     "     "      "                                     9-10 4e-09   --      --     "     "      "                                    11-12 4e-08   --      --     "     "      "                                    13-14 4e-07   --      --     "     "      "                                    15-16 4e-06   --      --     "     "      "                                    17-18 4e-05   --      --     "     "      "                                    19-20 4e-04   --      --     "     "      "                                    21-22 4e-03   --      --     "     "      "                                    23-24 4e-02   --      --     "     "      "                                    ______________________________________                                          *Stock concentration [M] of compound to be tested.                       

Components are added in the following order: test compound, radioligand, buffer or tissue to give a final volume of 2.0 ml. After adding the tissue homogenate, the tubes are thoroughly mixed and incubated at 25° C. for 120 minutes. At the end of 120 minutes, the samples are filtered through GF/B glass fiber filters (Whatman) using a 24 sample cell harvester (Brandel) under a vacuum of 15 mm Hg. The tubes are washed with 5×3 ml ice-cold NaKPB. The filters are then placed in scintillation vials with 10 ml of scintillation cocktail (Beckman HP or HP/B), allowed to stand overnight, shaken and then counted. Specific binding is calculated as Total--NS (non-specific). The percent inhibition of specific binding is then calculated and the Ki values computed using either the LIGAND or LUNDON software packages for competition binding. The results of this test on representative compounds of this invention appear in Table I.

[³ H]-Cis-methyldioxolane Binding Assay (High Affinity)

This assay is utilized is conjunction with ³ H-QNB binding to evaluate high affinity agonist binding and antagonist properties of CNS cholinergic agents. The procedure was adapted from Vickroy, T. W., Roeske, W. R, and Yamamura, H. I, J. Pharmacol. Exp. Ther. 229: 747-755 (1984). This is a rapid filtration assay that is set up to label only the high affinity agonist conformation of the muscarinic cholinergic receptor.

Tissue Preparation:

Rats are sacrificed by decapitation and the brain removed and placed on ice. The cerebral cortex is dissected on a cold stage, weighed and homogenized (Polytron, setting 5.5 with PT-10 saw-tooth generator for 15 seconds) in 50 volumes (wet wt/vol) of ice-cold 10 mM (8.1 mM Na₂ HPO₄, 1.9 mM KH₂ PO₄) sodium-potassium phosphate buffer (NaKPB), pH 7.4. The homogenate is placed in an ice bath for 30 seconds and homogenized again as above. This procedure is repeated once again for a total of three times. The resulting homogenate is then diluted 1:3000 (original wet wt/vol) with ice-cold NaKPB for use in the assay. The final protein content per 2.0 ml of incubation mixture is 0.1 mg.

Dilution of Compounds:

A stock solution of Atropine is prepared at 0.2 mM to define non-specific binding (1 μM final conc). Test compounds are prepared at 40 mM (final conc 1 mM) in buffer (if water soluble) or in absolute ethanol--1N HCl (1:1, v/v) and serially diluted to the desired concentrations. In general, dose-response profiles are examined between 1 mM and 1 pM final concentrations.

Preparation of ³ -H-CD:

³ H-CD (NEN, NET-647; specific activity=55.5 Ci/mmol) is diluted to 20 nM with NaPB (final conc=1.0 nM, activity 75,000 cpm at a counting efficiency of 55%).

Technical Notes:

³ -H-CD adheres readily to both glass and plastic surfaces. To eliminate this problem (and the chance for introducing artifacts into the results), stock vials, pipette tips and all glass tubes are routinely treated with Prosil-28, a siliconizing agent, and oven dried prior to use in an assay. Additionally, the GF/B glass fiber filters are pro-soaked in an aqueous polyethylenimine (PEI) solution (0.1%, pH 7.0) prior to use.

All points in the inhibition curve (including total and non-specific binding) are always measured on single PEI treated filter strips to minimize filter-to-filter variability. (See Bruns, R. F., et al. Anal. Biochem. 132: 74-81 (1983) for the use of PEI treated filters in filtration receptor assays).

The ³ H-CD is prepared fresh in buffer just prior to use in the assay to avoid possible decomposition. It should be kept on an ice bath after dilution in buffer.

³ H-CD Binding Assay:

A typical protocol is outlined below:

    ______________________________________                                                                      Test                                                                           Com-                                              Tube          Buffer  Atropine                                                                              pound .sup.3 H-QNB                                                                          Tissue                               No.   ID*     μL   μL  μL μL  ml                                   ______________________________________                                         1-2   Total   50      --     --    100    1.85                                 3-4   NS      40      10     --    "      "                                    5-6   4e-11   --      --     50    "      "                                    7-8   4e-10   --      --     "     "      "                                     9-10 4e-09   --      --     "     "      "                                    11-12 4e-08   --      --     "     "      "                                    13-14 4e-07   --      --     "     "      "                                    15-16 4e-06   --      --     "     "      "                                    17-18 4e-05   --      --     "     "      "                                    19-20 4e-04   --      --     "     "      "                                    21-22 4e-03   --      --     "     "      "                                    23-24 4e-02   --      --     "     "      "                                    ______________________________________                                          *Stock concentration [M] of compound to be tested.                       

Components are added in the following order: test compound, radioligand, buffer or tissue to give a final volume of 2.0 ml. After adding the tissue homogenate, the tubes are thoroughly mixed and incubated at 25° C. for 120 minutes. At the end of 120 minutes, the samples are filtered through GF/B glass fiber filters (Whatman) using a 24 sample cell harvester (Brandel) under a vacuum of 15 mm Hg. The tubes are washed with 5×3 ml ice-cold NaKPB. The filters are then placed in scintillation vials with 10 ml of scintillation cocktail (Beckman HP or HP/B), allowed to stand overnight, shaken and then counted. Specific binding is calculated as Total--NS (non-specific). The percent inhibition of specific binding is then calculated and the Ki values computed using either the LIGAND or LUNDON software packages for competition binding. The results of this test on representative compounds of this invention appear in Table I.

                  TABLE 1                                                          ______________________________________                                         In vitro Binding Data                                                                                 .sup.3 H-QNB                                                                            .sup.3 H-CD                                    Compound               Ki uM    Ki uM                                          ______________________________________                                         2,2,2-Trifluoro-N-[4(1-pyrrolidinyl)-2-                                                               18.5     8.88                                           butynyl]acetamide monohydrochloride                                            N-[4-Dimethylamino)-2-butynyl]-2,2,2-                                                                 >100     6.10                                           trifluoroacetamide monohydrochloride                                           N-[(4-Diethylamino)-2-butynyl]-2,2,2-                                                                 >100     4.07                                           trifluoroacetamide monohydrochloride                                           (S)-N-[4-[2-[[[(1,1-Dimethylethyl]-                                                                   >100     41.4                                           dimethylsilyl]oxy]methyl]-1-pyrro-                                             lidinyl]-2-butynyl]-2,2,2-trifluoro-                                           acetamide                                                                      4-(1-Pyrrolidinyl)-2-butyn-1-amine                                                                    >100     13.0                                           dihydrochloride                                                                N,N-Dimethyl-2-butyne-1,4-diamine                                                                     >100     20.5                                           dihydrochloride                                                                N,N-Diethyl-2-butyne-1,4-diamine                                                                      >100     >100                                           dihydrochloride                                                                Racemic-1-[4-Dimethylamino)-2-butynyl]-                                                               >100     >100                                           3-hydroxy-3-methyl-2-pyrrolidinone                                             Racemic-3-Hydroxy-3-methyl-1-[4-(1-pyrro-                                                             8.6      5.70                                           lidinyl)-2-butynyl]-2-pyrrolidinone                                            Racemic 1-[4-(1-Dimethylamino)-2-                                                                     21       0.41                                           butynyl]-3-methyl-2-pyrrolidinone                                              Racemic 1-[4-(1-Diethylamino)-2-                                                                      6.0      5.1                                            butynyl]-3-methyl-2-pyrrolidinone                                              (S)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                                35.5     0.68                                           methyl-2-pyrrolidinone                                                         (R)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                                7.7      0.073                                          methyl-2-pyrrolidinone                                                         Racemic 1-[4-(1H-imidazol-1-yl)-2-                                                                    6.7      0.057                                          butynyl]-3-methyl-2-pyrrolidinone                                              Racemic 1-[4-(1-azetidinyl)-2-butynyl-3-                                                              2.0      0.054                                          methyl-2-pyrrolidinone                                                         [R-[(R*,R* and R*,S*)]]-1-[4-[2-[[[(1,1-                                                              2.5      5.6                                            Dimethylethyl)dimethylsilyl]methyl]-1-                                         pyrrolidinyl]-2-butynyl]-3-methyl-2-                                           pyrrolidinone                                                                  [R-(R*,R* and R*, S*)]-1-[4-(3-([(1,1-                                                                >100     >100                                           Dimethylethyl)dimethylsilyl]oxy]-1-                                            pyrrolidinyl]-2-butynyl]-3-methyl-2-                                           pyrrolidinone                                                                  (S)-1-[4-(Diethylamino)-2-butynyl]-3-                                                                 7.6      15.4                                           [[(1,1-dimethylethyl)dimethylsilyl]-                                           oxy]-2-pyrrolidinone                                                           (S)-1-(4-(1-Azetidinyl)-2-butynyl]-3-                                                                 5.8      5.6                                            [[(1,1-dimethylethyl)dimethylsilyl]-                                           oxy]-2-pyrrolidinone                                                           (R)-1-[4-(1-Azetidinyl)-2-butynyl]-3-                                                                 >100     >100                                           [[(1,1-dimethylethyl)dimethylsilyl]-                                           oxy]-2-pyrrolidinone                                                           (S)-3-([(1,1-Dimethylethyl)dimethyl-                                                                  >100     24.3                                           silyl]oxy]-1-[4-(1H-imidazol-1-yl)-2-                                          butynyl-2-pyrrolidinone                                                        (R)-3-[[(1,1-Dimethylethyl)dimethyl-                                                                  >100     14.0                                           silyl]oxy]-1-[4-(1H-imidazol-1-yl)-2-                                          butynyl]-2-pyrrolidinone                                                       (S)-3-Hydroxy-1-[4-(1H-imidazol-1-yl)-                                                                >100     0.12                                           2-butynyl]-2-pyrrolidinone                                                     1-[4-(1H-Imidazol-1-yl)-2-butynyl]-3-                                                                 >100     2.0                                            hydroxy-2-pyrrolidinone                                                        (S)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                                14.3     18.2                                           [[(1,1-Dimethylethyl)dimethylsilyl]-                                           oxy]-2-pyrrolidinone                                                           (S)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                                26.9     0.043                                          hydroxy-2-pyrrolidinone                                                        (R)-1-[4-(Dimethylamino)-2-butynyl]-3-                                                                104.7    0.54                                           hydroxy-2-pyrrolidinone                                                        (S)-3-[[(1,1-Dimethylethyl)dimethyl-                                                                  2.7      3.0                                            silyl]oxy]-1-[4-(1-pyrrolidinyl)-2-                                            butynyl]-2-pyrrolidinone                                                       (S)-3-Hydroxy-1-[4-(1-pyrrolidinyl)-2-                                                                1.7      0.007                                          butynyl]-2-pyrrolidinone                                                       (R)-3-Hydroxy-1-[4-(1-pyrrolidinyl)-2-                                                                3.4      0.125                                          butynyl]-2-pyrrolidinone                                                       (S)-3-Hydroxy-1-[4-[(2-hydroxyethyl)-                                                                 >100     1.82                                           methylamino]-2-butynyl]-2-pyrro-                                               lidinone                                                                       (R)-3-Hydroxy-1-[4-[(4-hydroxybutyl)-                                                                 >100     1.45                                           methylamino]-2-butynyl]-2-pyrro-                                               lidinone                                                                       [R-(R*,S*)]-3-(Acetyloxy)-1-[4-[2-                                                                    500      1.7                                            [[[(1,1-dimethylethyl)dimethylsilyl]-                                          oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-                                        2-pyrrolidinone                                                                [S-(R*,R*)]-3-(Acetyloxy)-1-[4-[2-                                                                    2.6      0.079                                          [[[(1,1-dimethylethyl)dimethylsilyl]-                                          oxy]methyl]-1-pyrrolidinyl]-2-                                                 butynyl]-2-pyrrolidinone                                                       [S-(R*,S*)]-3-(Acetyloxy)-1-[4-[2-                                                                    >100     4.2                                            [[[(1,1-dimethylethyl)dimethylsilyl]-                                          oxy]methyl]-1-pyrrolidinyl]-2-                                                 butynyl]-2-pyrrolidinone                                                       [R-(R*,R*)]-3-Acetyloxy)-1-[4-[2-                                                                     >100     10.1                                           [[[(1,1-dimethylethyl)dimethylsilyl]-                                          oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-                                        2-pyrrolidinone                                                                (S)-3-(Acetyloxy)-1-[4-[2-(hydroxy-                                                                   >100     16.2                                           ethyl)methylamino]-2-butynyl]-2-                                               pyrrolidinone                                                                  (R)-3-(Acetyloxy)-1-[4-[(2-hydroxy-                                                                   >100     28.3                                           ethyl)methylamino]-2-butynyl]-2-pyrro-                                         lidinone                                                                       (S)-3-(Acetyloxy)-1-[4-[(4-hydroxy-                                                                   >100     8.21                                           butyl)methylaminol-2-butynyl]-2-pyrro-                                         lidinone                                                                       [R-(R*,S*)]-1-[4-[2-[[[(1,1-                                                                          0.5      0.47                                           Dimethylethyl)dimethylsilyl]oxy]-                                              methyl-]-1-pyrrolidinyl]-2-butynyl]-                                           3-hydroxy-2-pyrrolidone                                                        [S-(R*,R*)]-1-[4-[2-[[[(1,1-                                                                          0.4      0.14                                           Dimethylethyl)dimethylsilyl]oxy]-                                              methyl]-1-pyrrolidinyl]-2-butynyl]-                                            3-hydroxy-2-pyrrolidinone                                                      [S-(R*,S*)]-1-[4-[2-[[[(1,1-Dimethyl-                                                                 198      1.7                                            ethyl)dimethylsilyl]oxy]methyl]-1-                                             pyrrolidinyl]-2-butynyl]-3-hydroxy-                                            2-pyrrolidinone                                                                [R-(R*,R*)]-1-[4-[27[[((1,1-Dimethyl-                                                                 >100     4.2                                            ethyl)dimethylsilyl]oxy]methyl]-1-                                             pyrrolidinyl]-2-butynyl]-3-hydroxy-2-                                          pyrrolidinone                                                                  (R)-3-Hydroxy-1-[4-[(2-hydroxyethyl)-                                                                 >100     1.80                                           methylamino]-2-butynyl]-2-pyrro-                                               lidinone                                                                       (S)-3-Hydroxy-1-[4-[(4-hydroxybutyl)-                                                                 >100     1.3                                            methylaminc]-2-butynyl]-2-pyrro-                                               lidinone                                                                       [S-(R*,S*)]-3-Hydroxy-1-[4-[2-                                                                        >100     2.60                                           (hydroxymethyl)-1-pyrrolidinyl]-2-                                             butynyl]-2-pyrrolidinone                                                       [S-(R*,R*)]-3-Hydroxy-1-[4-[2-                                                                        >100     34.3                                           (hydroxymethyl)-1-pyrrolidinyl]-2-                                             butynyl]-2-pyrrolidinone                                                       (S)-3-(Methylthio)-1-[4-                                                                              53       1.04                                           (1-pyrrolidinyl)-2-butynyl]-2-                                                 pyrrolidinone                                                                  (R)-3-(Methylithio)-1-[4-(1-pyrro-                                                                    3.6      1.4                                            lidinyl)-2-butynyl]-2-pyrroli-                                                 dinone                                                                         (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                                  >100     6.4                                            3-(methylthio)-2-pyrrolidinone                                                 (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                                  108      6.1                                            3-(methylthio)-2-pyrrolidinone                                                 (S)-N,N,N-Trimethyl-4-(3-(methylthio)-                                                                1.8      0.31                                           2-oxo-1-pyrrolidinyl]-2-butyn-1-                                               aminium iodide                                                                 (S)-3-Azido-1-[4-(1-pyrrolidinyl)-2-                                                                  3.14     0.16                                           butynyl]-2-pyrrolidinone                                                       (S)-3-Amino-1-[4-(1-pyrrolidinyl)-                                                                    73.6     0.41                                           2-butynyl]-2-pyrrolidinone dihydro-                                            chloride                                                                       (R)-3-Azido-1-[4-(1-pyrrolidinyl)-                                                                    28       0.21                                           2-butynyl]-2-pyrrolidinone                                                     (R)-3-Amino-1-[4-(1-pyrrolidinyl)-                                                                    6.1      0.35                                           2-butynyl]-2-pyrrolidinone dihydro-                                            chloride                                                                       (S)-3-Azido-1-[4-(dimethylamino)-                                                                     >100     0.63                                           2-butynyl]-2-pyrrolidinone                                                     (R)-3-Azido-1-[4-(dimethylamino)-                                                                     >100     0.50                                           2-butynyl]-2-pyrrolidinone                                                     (S)-4-(3-Azido-2-oxo-1-pyrro-                                                                         1.6      0.045                                          lidinyl)-N,N,N-trimethyl-2-butyn-                                              1-aminium iodide                                                               (R)-4-(3-Azido-2-oxo-1-pyrro-                                                                         0.8      0.039                                          lidinyl)-N,N,N-trimethyl-2-butyn-1-                                            aminium iodide                                                                 (S)-3-Amino-1-[4-(dimethylamino)-                                                                     >100     2.6                                            2-butynyl]-2-pyrrolidinone dihydro-                                            chloride                                                                       (R)-3-Amino-1-[4-(dimethylamino)-2-                                                                   >100     0.89                                           butynyl]-2-pyrrolidinone dihydro-                                              chloride                                                                       (S)-2-Methylpropanoic acid 1-[4-                                                                      610      ND                                             (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                                             (S)-2,2-Dimethylpropanoic acid 1-                                                                     484      38.8                                           [4-(dimethylamino)-2-butynyl]-2-oxo-                                           3-pyrrolidinyl ester                                                           (S)-Decanoic acid 1-[4-(dimethyl-                                                                     0.6      0.023                                          amino)-2-butynyl]-2-oxo-3-pyrro-                                               lidinyl ester                                                                  (S)-Carbonic acid 1-[4-(dimethylamino)-                                                               10       0.306                                          2-butynyl]-2-oxo-3-pyrrolidinyl octyl                                          ester                                                                          (S)-Carbonic acid 1-[4-(dimethylamino)-                                                               15.1     2.16                                           2-butynyl]-2-oxo-3-pyrrolidinyl] methyl                                        ester                                                                          (S)-N,N,N-Trimethyl-4-[2-oxo-3-[(1-                                                                   0.003    0.156                                          oxodecyl)oxy]-1-pyrrolidinyl-2-butyn-                                          1-aminium iodide                                                               (S)-N,N,N-Trimethyl-4-[3-(2-methyl-1-                                                                 64.3     6.96                                           oxopropoxy)-2-oxo-1-pyrrolidinyl]-2-                                           butyn-1-aminium iodide                                                         (S)-4-[3-(2,2-Dimethyl-1-oxopropoxy)-                                                                 478      7.80                                           2-oxo-1-pyrrolidinyl]-N,N,N-trimethyl-                                         2-butyn-1-aminium iodide                                                       (S)-N,N,N-Trimethyl-4-[3-[[(octyloxy)-                                                                0.1      0.013                                          carbonyl]oxy]-2-oxo-1-pyrrolidinyl]-2-                                         butyn-1-aminium iodide                                                         (S)-2-Methylpropanoic acid 2-oxo-1-[4-                                                                7.2      0.162                                          (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                           lidinyl ester                                                                  (S)-2,2-Dimethylpropanoic acid 2-oxo-                                                                 4.6      0.37                                           1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                            pyrrolidinyl ester                                                             (S)-3-[[(Methylamino)carbonyl]oxy-1-[4-                                                               433      >100                                           (1-pyrrolidinyl)-2-butynyl]-2-pyrro-                                           lidinone                                                                       (S)-Dimethylcarbamic acid 2-oxo-1-[4-                                                                 40.3     9.56                                           (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                           lidinyl ester                                                                  (S)-Carbonic acid hexyl 2-oxo-1-[4-                                                                   1.7      0.015                                          (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                           lidinyl ester                                                                  (S)-Carbonic acid methyl                                                                              5.4      0.053                                          2-oxo-1-[4-(1-pyrrolidinyl)-2-buty-                                            nyl]-3-pyrrolidinyl ester                                                      (S)-Carbonic acid methyl 2-oxo-                                                                       10.4     0.23                                           1-[4-(1-pyrrolidinyl)-2-butynyl]-                                              3-pyrrolidinyl ester                                                           (R)-Propanoic acid 2-methyl-1-[4-                                                                     711      26.0                                           (dimethylamino)-2-butynyl]-2-oxo-                                              3-pyrrolidinyl ester                                                           (R)-2,2-Dimethylpropanoic acid                                                                        404      ND                                             1-[4-(dimethylamino)-2-butynyl]-2-                                             oxo-3-pyrrolidinyl ester                                                       (R)-Decanoic acid 1-[4-(dimethyl-                                                                     >100     0.73                                           amino)-2-butynyl]-2-oxo-3-pyrro-                                               lidinyl ester                                                                  (R)-Octylcarbamic acid 1-[4-(di-                                                                      32       1.43                                           methylamino)-2-butynyl]-2-oxo-3-                                               pyrrolidinyl ester                                                             (R)-Carbonic acid 1-[4-(dimethyl-                                                                     52       3.07                                           amino)-2-butynyl]-2-oxo-3-pyrro-                                               lidinyl methyl ester monohydro-                                                chloride                                                                       (R)-Carbonic acid 1-[4-(dimethyl-                                                                     1.5      1.04                                           amino)-2-butynyl]-2-oxo-3-pyrro-                                               lidinyl octyl ester                                                            (R)-N,N,N-Trimethyl-4-[3-(2-methyl-                                                                   45       0.24                                           1-oxopropoxy)-2-oxo-1-pyrrolidinyl]-                                           2-butyn-1-aminium iodide                                                       (R)-4-[3-(2,2-Dimethyl-1-oxopropoxy)-                                                                 >100     1.22                                           2-oxo-1-pyrrolidinyl]-N,N,N-trimethyl-                                         2-butyn-1-aminium iodide                                                       (R)-4-[2-Oxo-3-((1-oxodecyl)oxy]-                                                                     0.2      0.050                                          1-pyrrolidinyl]-N,N,N-trimethyl-2-                                             butyn-1-aminium iodide                                                         (R)-N,N,N-Trimethyl-4-[3-[[(octyl-                                                                    0.5      0.49                                           amino)carbonyl]oxyl-2-oxo-1-pyrro-                                             lidinyl]-2-butyn-1-aminium iodide                                              (R)-N,N,N-Trimethyl-4-[3-[[(octyloxy)-                                                                0.2      0.010                                          carbonyl]oxy]-2-oxo-1-pyrrolidinyl]-                                           2-butyn-1-aminium iodide                                                       (R)-2-Methylpropanoic acid 2-oxo-1-                                                                   87       0.135                                          [4-(1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                        lidinyl ester                                                                  (R)-2,2-Dimethylpropanoic acid 2-oxo-                                                                 10.2     0.50                                           1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                            pyrrolidinyl ester                                                             (R)-Decanoic acid 2-oxo-1-[4-(1-pyrro-                                                                0.2      0.097                                          lidinyl)-2-butynyl]-3-pyrrolidinyl                                             ester                                                                          (R)-Carbonic acid 2-oxo-1-[4-(1-pyrro-                                                                1.4      0.11                                           lidinyl)-2-butynyl]-3-pyrrolidinyl                                             phenymethyl ester                                                              (R)-Octylcarbamic acid 2-oxo-1-[4-(1-                                                                 0.2      0.24                                           pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                        ester                                                                          (R)-Carbonic acid octyl 2-oxo-1-[4-                                                                   0.1      0.076                                          (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                           lidinyl ester                                                                  (R)-Carbonic acid methyl 2-oxo-1-[4-                                                                  27.3     0.35                                           (1-pyrrolidinyl)-2-butynyl]-3-pyrro-                                           lidinyl ester                                                                  (S)-Decanoic acid 2-oxo-1-[4-(1-pyrro-                                                                0.035    0.33                                           lidinyl)-2-butynyl]-4-pyrrolidinyl                                             ester                                                                          (S)-Carbonic acid methyl 2-oxo-1-[4-(1-                                                               1.8      0.85                                           pyrrolidiny)-2-butynyl]-4-pyrrolidinyl                                         ester                                                                          (S)-Octylcarbamic acid 2-oxo-1-[4-(1-                                                                 0.13     0.35                                           pyrrolidinyl-2-butynyl]-4-pyrrolidinyl                                         ester                                                                          ______________________________________                                    

Those compounds which have ³ H-CD and ³ H-QNB Ki values of less than 100 μM are considered active. The compounds tested can be divided into 3 categories: 1. compounds which are products or therapeutic agents; 2. compounds which are a prodrug form of the products or therapeutic agents and 3. compounds which are reaction intermediates.

The term prodrug signifies a compound which is to some degree chemically and biochemically labile. When the prodrug is metabolized in the body, the active product or therapeutic agent is released or unmasked.

The pharmaceutical preparations of the present invention may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.

The effective dosage of active ingredient employed may vary with the particular compound employed, the mode of administration, and the severity of the condition being treated. In general, however, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.02 mg to about 100 mg/kg of patient body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most patients, the total daily dosage is from about 1 mg to about 5,000 mg, preferably from about 1 mg to 20 mg. Dosage forms suitable for internal use comprise from about 0.25 to 5.0 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

A decided practical advantage is that these active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes if necessary. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut, and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exits. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated.

The use of the radioligand binding assays (³ H-QNB and ³ H-CD) to characterize the hydroxylated oxotremorine derivatives provides a useful first approximation for,the evaluation of the muscarinic agonist-like profile of a test compound. However, in using a prodrug methodology, intrinsic activity will not be observed until in vivo hydrolysis or metabolism to the active compound occurs. Therefore, radioligand binding data, performed on the carbonyl derivatives, will not provide leading information. As a result, the observed overt effects after oral administration to rats of the test carbonyl derivative, relative to its corresponding hydroxylated oxotremorine compound, became the primary in vivo pharmacological measure. These in vivo overt effects are attributed to the peripheral acetylcholine-like effects of the compound, such as salivation, tremor and diarrhea. The in vivo overt effects also providing dosing information for the behavioral tests of cognitive improvement.

The passive avoidance produce (Olson S. Wenk, G. Phychopharmacology: The Third Generation of Progress, ed. Meltzer, H. Y. Raven Press, New York 1987; Rusted, J. M.; Warburton, D. M. Neuropsychobiology 1989, 21, 31) is used as the primary behavioral model to measure potential memory enhancing effect of the compound. The test performed in rats uses the antagonism of atropine-induced deficits (12 mg/kg s.c.) in retention of a noxious consequence (foot shock). The behavioral test provides a reasonably rapid assessment that, in conjunction with the evaluation of side effects, can serve as an initial basis for determining the likely potential of these compounds for clinical efficacy.

In the atropine disruption of the passive avoidance procedure, rats are injected s.c. with 12 mg/kg of atropine and placed into one side of a two-compartment chamber. The side into which the rats are placed is brightly illuminated. When the rat enters the darkened portion of the experimental chamber a guillotine door separating the two compartments is lowered and the rat receives a 3-sec 0.75 mA electric shock. Rats receiving saline under this procedure do not enter the darkened portion of the chamber when tested 24 hours following this initial experience, whereas rats receiving atropine enter the chamber with a very brief latency, similar to that obtained on the first exposure day. The test compounds are evaluated for their ability to reverse the passive avoidance deficits induced by atropine. For the atropine-reversal assessment, a range of doses of the test compounds is administered 50 minutes prior to the atropine, which is administered 20 minutes before the initial experimental session. Doses of the test compounds are suspended in methylcellulose and administered orally via a stainless steel feeding tube. The test session on day two is conducted without drug administration and without shock. The rat is allowed 3 minutes no enter the darkened portion of the chamber at which time it is removed. The latency (sec) to enter the darkened chamber on the second test day is the primary measure of the ability of the test compound to reverse atropine-induced deficits in the passive avoidance response. Compounds which produce a significant latency, when compared to the saline controls, are considered active.

In general, the carbonyl derivatives of the hydroxylated oxotremorines are orally active in the passive avoidance procedure at doses that are lower than those which produce corresponding cholinergic side effects. In those compounds where activity in the passive avoidance procedure is not noted, significant side effects are observed which are assumed to mask the desired pharmacological effect.

                  TABLE IB                                                         ______________________________________                                         in Vivo Pharmacological Data                                                                       Passive   Side Effect                                                          Avoidance Profile                                                              active    minimum                                                              dose or   effective                                                            range     dose (MED)                                                           (rat) po  (rat) po                                         Compound Name       μ mol/kg                                                                              μ mol/kg                                      ______________________________________                                         (S)-Butanoic acid 1-[4-       8.0                                              (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (S)-Hexanoic acid 1-[4-       5.9                                              (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (S)-Octanoic acid 1-[4-       8.0                                              (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (S)-Ethylcarbamic acid 1-[4-                                                                       13        >510                                             (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (S)-Butylcarbamic acid 1-[4-                                                                        12-100   >493                                             (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (S)-Hexylcarbamic acid 1-[4-  >510                                             (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (S)-Octylcarbamic acid 1-[4-                                                                       1-3       >520                                             (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (S)-1-[4-(Dimethylamino)-2-   2.2                                              butynyl]-2-oxo-3-pyrrolidinyl                                                  carbonic acid ethyl ester                                                      (S)-1-[4-(Dimethylamino)-2-                                                                        12-51     32                                               butynyl]-2-oxo-3-pyrrolidinyl                                                  carbonic acid butyl ester                                                      (S)-1-[4-(Dimethylamino)-2-                                                                        26        8                                                butynyl]-2-oxo-3-pyrrolidinyl                                                  carbonic acid butyl ester                                                      (R)-Butanoic acid 1-[4-                                                                             13-105   127                                              (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (R)-Hexanoic acid 1-[4-                                                                            10-84     255                                              (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (R)-Octanoic acid 1-[4-                                                                            13        508                                              (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (R)-Ethylcarbamic acid 1-[4-  >510                                             (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (R)-Butylcarbamic acid 1-[4-                                                                       3-7       >340                                             (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       (R)-Hexylcarbamic acid 1-[4-                                                                        7-58     >530                                             (dimethylamino)-2-butynyl]-2-                                                  oxo-3-pyrrolidinyl ester                                                       R)-1-[4-(Dimethylamino)-2-                                                                         110       258                                              butynyl]-2-oxo-3-pyrrolidinyl                                                  carbonic acid ethyl ester                                                      (R)-1-[4-(Dimethylamino)-2-                                                                        1.6, 3.1  127                                              butynyl]-2-oxo-3-pyrrolidinyl                                                  carbonic acid ethyl ester                                                      (R)-1-[4-(Dimethylamino)-2-                                                                         6, 46    254                                              butynyl]-2-oxo-3-pyrrolidinyl                                                  carbonic acid ethyl ester                                                      (S)-Butanoic acid 2-oxo-1-[4- 1.7                                              (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                                             (S)-Hexanoic acid 2-oxo-1-[4- 1.8                                              (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                                             (S)-Octanoic acid 1-[4-(1-    14                                               (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                                             (S)-Decanoic acid 2-oxo-1-[4-                                                                       6        14                                               (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                                             (S)-Ethylcarbamic acid 2-oxo-                                                                      22-90     >490                                             1-[4-(1-pyrrolidinyl)-2-                                                       butynyl]-3-pyrrolidinyl ester                                                  (S)-Butylcarbamic acid 2-oxo-                                                                       22-180   225                                              [4-(1-pyrrolidinyl)-2-                                                         butynyl]-3-pyrrolidinyl ester                                                  (S)-Hexylcarbamic acid 2-oxo-                                                                      45        >450                                             1-[4-(1-pyrrolidinyl)-2-                                                       butynyl]-3-pyrrolidinyl ester                                                  (S)-Octylcarbamic acid 2-oxo-                                                                      11, 45    >450                                             1-[4-(1-pyrrolidinyl)-2-                                                       butynyl]-3-pyrrolidinyl ester                                                  (S)-2-Oxo-1-[4-(1-            1.7                                              pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl carbonic acid                                                     ethyl ester                                                                    (S)-2-Oxo-1-[4-(1-   1-10     0.9                                              pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl carbonic acid                                                     butyl ester                                                                    (S)-2-Oxo-1-[4-(1-            28                                               pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl carbonic acid                                                     octyl ester                                                                    (R)-Butanoic acid 2-oxo-1-[4-                                                                       5-18     7.2                                              (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                                             (R)-Hexanoic acid 2-oxo-1-[4-                                                                      11, 22    7.0                                              (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                                             (R)-Octanoic acid 2-oxo-1-[4-                                                                      2-5       14                                               (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                                             (R)-Ethylcarbamic acid 2-oxo-                                                                      22        28                                               1-[4-(1-pyrrolidinyl)-2-                                                       butynyl]-3-pyrrolidinyl ester                                                  (R)-Butylcarbamic acid 2-oxo-                                                                      28        >243                                             1-[4-(1-pyrrolidinyl)-2-                                                       butynyl]-3-pyrrolidinyl ester                                                  (R)-Hexylcarbamic acid 2-oxo-                                                                      90        >450                                             1-[4-(1-pyrrolidinyl)-2-                                                       butynyl]-3-pyrrolidinyl ester                                                  (R)-2-Oxo-1-[4-(1-  14        14                                               pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl carbonic acid                                                     butyl ester                                                                    (R)-2-Oxo-1-[4-(1-  23        7                                                pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl carbonic acid                                                     hexyl ester                                                                    ______________________________________                                    

The following examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations, and the invention should not be construed as being limited by chemical reactions and conditions they express. No attempt has been made to optimize the yields obtained in these reactions, and it would be obvious to one skilled in the art that variations in reaction times, temperatures, solvents, and/or reagents could increase the yields.

EXAMPLE 1 2,2,2-Trifluoro-N-2-propynylacetamide

To a stirring 0° C. solution of 15.0 g of propargylamine in 200 ml of methylene chloride is added, dropwise, a solution of 63.0 g of trifluoroacetic anhydride in 50 ml of methylene chloride. The reaction is stirred at room temperature for 1 hour followed by the addition of 100 ml of water. The mixture is washed with 150 ml of 1N hydrochloric acid and 150 ml of saturated sodium bicarbonate. The organic layer is dried, filtered and concentrated in vacuo. The residue is distilled under vacuum (0.2 mm Hg) at 40° C. to give 32.1 g of the desired product as a colorless oil.

EXAMPLE 2 2,2,2-Trifluoro-N-[4-(1-pyrrolidinyl)-2-butynyl]acetamide monohydrochloride

A mixture of 50.0 g of product from Example 1, 47.1 g of pyrrolidine, 24.9 g of paraformaldehyde, 50 ml of glacial acetic acid, 0.5 g of cuprous chloride and 500 ml of dry dioxane is heated at reflux temperature for 20 minutes. The reaction mixture is concentrated in vacuo and made basic to pH 10-11 with concentrated ammonium hydroxide. The aqueous layer is extracted with methylene chloride. The combined organic extracts are dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo. The residue is distilled under vacuum (0.3 mm Hg) at 110°-120° C. to give the desired product as a yellow oil. Eight grams of oil is dissolved in 1N methanolic hydrogen chloride. The resulting solid is collected and recrystallized from methyl alcohol/diethyl ether to give 1.7 g of the desired product as the monohydrochloride.

MP 125°-127° C.

Following the general procedure of Example 2 and using 2,2,2-trifluoro-N-2-propynylacetamide

(Example 1), the products of Examples 3-5, found in Table II, are prepared.

                                      TABLE II                                     __________________________________________________________________________                               MP°C./or [alpha].sub.D.sup.26                 Example                                                                             Reactant Product     (methylene chloride)                                 __________________________________________________________________________     3    Dimethylamine                                                                           N-[4-Dimethylamino)-2-                                                                     112-114°                                                    butynyl]-2,2,2-trifluoro-                                                      acetamide monomhydro-                                                          chloride                                                         4    Diethylamine                                                                            N-[4-(Diethylamino)-2-                                                                     111-112°                                                    butynyl]-2,2,2-trifluoro-                                                      acetamide monohydro-                                                           chloride                                                         5    (S)-2-[[[1,1-                                                                           (S)-N-[4-[2-[[[(1,1-                                                                       [alpha].sub.D.sup.26 = -41°                        (Dimethylethyl)-                                                                        Dimethylethyl]-                                                       dimethylsilyl]oxy-                                                                      dimethylsilyl]oxy]-                                                   methyl]-1-                                                                              methyl]-1-pyrrolidinyl]-                                              pyrrolidinyl]-2-                                                                        2-butynyl]-2,2,2-                                                     butynyl]-2,2,2-                                                                         trifluoroacetamide                                                    trifluoroacetamide                                                        __________________________________________________________________________

EXAMPLE 6 4-(1-Pyrrolidinyl)-2-butyn-1-amine dihydrochloride

A mixture of 50.0 g of product from Example 2 and 267 ml of 4N hydrochloric acid is heated at reflux temperature. After 2 hours, the progress of the reaction is checked by thin layer chromatography, 70 ml of concentrated hydrochloric acid is added and the mixture is heated at reflux temperature overnight. The reaction is concentrated in vacuo and the residue is washed with methylene chloride. The aqueous layer is cooled, made basic with 10N sodium hydroxide and extracted with methylene chloride. The combined organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo to give 27.8 g of a dark oil. The oil is treated with 450 ml of 1N methanolic hydrogen chloride and concentrated in vacuo. The resulting solid is recrystallized from methyl alcohol/diethyl ether to give 31.2 g of the desired product as off-white crystals.

MP 192°-193° C.

Following the general procedure of Example 6, the products of Examples 7-8, found in Table III, are prepared.

                                      TABLE III                                    __________________________________________________________________________          Starting                                                                  Example                                                                             Material                                                                             Reactant                                                                               Product     MP °C.                                   __________________________________________________________________________     7    Example 3                                                                            Hydrochloric                                                                           N,N-Dimethyl-2-butyne-                                                                     181-183°                                            acid    1,4-diamine                                                                    dihydrochloride                                             8    Example 4                                                                            Hydrochloric                                                                           N,N-Diethyl-2-butyne-                                                                      149-150°                                            acid    1,4-diamine                                                                    dihydrochloride                                             __________________________________________________________________________

EXAMPLE 9 (S)-4-[2-[[[(1,1-Dimethylethyl)dimethylsily]oxy]methyl]-1-pyrrolidinyl]-2-butyn-1-amine

To a stirring solution of 5.76 g of product from Example 5 in 145 ml of tetrahydrofuran and 3 ml of water is added 5.76 g of sodium borohydride. The reaction is stirred at room temperature for 18 hours followed by concentration in vacuo to half volume. Saturated sodium chloride is added and the mixture is extracted with methylene chloride. The organic layer is concentrated in vacuo to give a viscous oil. The oil is purified by chromatography (alumina, grade 2.5, 1% methyl alcohol/methylene chloride) to give 1.92 g of the desired product as a colorless oil.

[α]_(D) ²⁶ =-56° (methyl alcohol, c=1.016%).

EXAMPLE 10 Racemic 1-[4-(Dimethylamino)-2-butynyl]-3-hydroxy-3-methyl-2-pyrrolidinone

A solution of 5.0 g of 2-phenylcyclohexanol, 8.25 g of pyruvic acid, 0.3 g of p-toluenesulfonic acid and 100 ml of toluene is heated at reflux temperature. A Dean-Stark trap is used to collect the water distillate. The reaction is cooled, washed with aqueous sodium bicarbonate, dried and the filtrate concentrated in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride) to give 5.5 g of trans-2-phenylcyclohexylpyruvate.

To a -78° C. solution of 15 g of trans-2phenylcyclohexylpyruvate in 400 ml of methylene chloride is added, dropwise via syringe, 9.0 g of stannic chloride. The solution is stirred for 10 minutes followed by the addition of 25 ml of allyltrimethylsilane in 15 ml of methylene chloride. The reaction is stirred at -78° C. for 1 hour. Eighteen ml of triethylamine is added and the mixture allowed to warm to room temperature. Twenty-five ml of water and 10 g of diatomaceous earth is added and the mixture filtered through a pad of diatomaceous earth. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, 10% ethyl acetate/petroleum ether) to give 16 g of trans-2-phenylcyclohexyl-2-hydroxy-2-methyl-4-pentenoate.

A stream of ozone is passed through a solution of 5.0 g of trans-2-phenylcyclohexyl-2-hydroxy-2-methyl-4-pentenoate in 150 ml of methylene chloride until a blue color persists. The blue color is discharged with a stream of argon. Two ml of dimethylsulfide is added and the solution allowed to warm to room temperature. The solution is concentrated to approximately 75 ml, washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is diluted with 100 ml of methyl alcohol and successively treated with 3.2 g of sodium acetate, 10 ml of acetic acid and 3.0 g of N,N-dimethyl-2-butyne-1,4-diamine hydrochloride. The resulting reaction mixture is stirred at room temperature for 10 minutes. One and one-half grams of sodium cyanoborohydride is added, in portions, over the next 2 hours and the reaction is stirred overnight at room temperature. The mixture is concentrated in vacuo, partitioned between methylene chloride and saturated aqueous sodium carbonate, and the layers separated. The organic layer is dried and concentrated in vacuo. The residue is a mixture of the product and its ring open form 4-[[4-(dimethylamino)-2-butynyl]amino]-2-methylbutanoic acid ethyl ester. The oil which is a mixture of the product and its ring open form, 0.030 g of p-toluenesulfonic acid and 150 ml of ethyl alcohol is heated at reflux temperature for 36 hours. The solution is concentrated in vacuo and the residue purified by chromatography (alumina, 1-5% methyl alcohol/methylene chloride) to give 1.4 g of the desired product as a waxy solid. MP 58°-59° C.

CI-MS: m/z 211 (M+H⁺).

EXAMPLE 11 Racemic 3-hydroxy-3-methyl-1-[4-(1-pyrrolidinyl) 2-butynyl]-2-pyrrolidinone

The title compound is prepared by the procedure of Example 10 up to and including the ozonization procedure with the substitution of the product from Example 6 for the product of Example 7.

CI-MS:m/z 237 (M+H⁺).

EXAMPLE 12 (S)-4-(1-Methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone

To a -78° C. solution of 5.0 g of 4-(1-methylethyl)-2-oxazolidinone in 80 ml of tetrahydrofuran is added, dropwise, 15.5 ml of 2.5M n-butyl lithium in hexane. After stirring for 30 minutes, a solution of 4.8 g of 4-pentenyl chloride in 30 ml of tetrahydrofuran is added, dropwise, and the resulting solution is stirred at -78° C. for 3.5 hours. The reaction is diluted with aqueous ammonium chloride and diethyl ether. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, 25% ethyl acetate/petroleum ether) to give 5.8 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =+79° (methylene chloride)

EXAMPLE 13 (4R-cis)-5-Methyl-3-(1-oxo-4-pentenyl)-4-phenyl-2-oxazolidinone

The title compound is prepared by the procedure of Example 12, using 8.0 g of (4R-cis)-5-methyl-3,4-phenyl-2-oxazolidinone,18 ml of 2.5M n-butyl lithium and 5.0 g of 4-pentenyl chloride to give 10.3 g of the desired product as colorless crystals. MP 69°-70° C.

[α]_(D) ²⁶ =+34° (methylene chloride).

EXAMPLE 14 [S-(R*,R*)]-4-(1-Methylethyl)-3-(2-methyl-1-oxo-4-pentenyl)-2-oxazolidinone

To a -78° C. solution of 2.0 g of product from Example 12 in 40 ml of tetrahydrofuran is added, dropwise, 7.6 ml of 1.5M lithium diisopropylamide in tetrahydrofuran. The reaction is stirred at -78° C. for 1 hour, 1.8 ml of iodomethane is added and the mixture stirred at -20° C. for 3 hours. The reaction is diluted with aqueous ammonium chloride and methylene chloride. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, 25% ethyl acetate/hexane) to give 1.3 g of the product as colorless crystals. MP 54°-55° C.

[α]_(D) ²⁶ =+108° (methylene chloride).

EXAMPLE 15 [4R-[3(R*), 4 alpha,5 alpha]]-5-Methyl-3-2-methyl-1-oxo-4-pentenyl)-4-phenyl-2-oxazolidinone

The title compound is prepared by the procedure of Example 14, using 4.0 g of (4R-cis)-5-methyl-1-3-(-oxo-4-pentenyl)-4-phenyl-2-oxazolidinone, 12.3 ml of 1.5M lithium diisopropylamide and 1.8 ml of iodomethane to give 2.9 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =-2° (methylene chloride).

EXAMPLE 16 (S)-2-Methyl-4-pentenoic acid phenylmethyl ester

To a 0° C. solution of 5.1 g of benzyl alcohol in 50 ml of tetrahydrofuran is added, dropwise, 3.8 ml of 2.5M n-butyl lithium in hexane. To this mixture is added, via cannula, a solution of 3.5 g of [S-(R*,R*)]4-(1-methylethyl)-3-(2-methyl-1-oxo-4-pentenyl)-2-oxazolidinone in 100 ml of tetrahydrofuran. The resulting solution is stirred at 0° C. for 2 hours. The reaction is diluted with saturated aqueous ammonium chloride and methylene chloride. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel methylene chloride) to give 2.9 g of the desired product as a colorless oil.

[α]_(D) ²⁶ =+3° (methylene chloride).

EXAMPLE 17 (R)-2-Methyl-4-pentenoic acid phenylmethyl ester

The title compound is prepared by the procedure of Example 16 using, 3.5 g of [4R-[3(R*),4 alpha, 5 alpha]]-5-methyl-3-(2-methyl-1-oxo-4-pentenyl)-4-phenyl-1-2-oxazolidinone, 4.2 g of benzyl alcohol and 3.1 ml of 2.5M n-butyl lithium to give 2.4 g of the desired product as a colorless oil.

[α]_(D) ²⁶ =-2° (methylene chloride).

EXAMPLE 18 Racemic 2-methyl-4-pentenoic acid phenylmethyl ester

To 1.2 L of ethyl alcohol under an atmosphere of argon is added, in portions, 14.9 g of sodium. After all the sodium is dissolved, 103 ml of diethyl methylmalonate is added and the reaction is stirred at room temperature for 30 minutes. Fifty-one ml of allyl bromide is added, dropwise, and the resulting solution is stirred at room temperature for 18 hours. The reaction is concentrated in vacuo and the residue partitioned between water and methylene chloride. The organic layer is dried and concentrated in vacuo to give 77.7 g of methyl 2-propenylpropane dicarboxylic acid diethyl ester.

A mixture of 77.7 g of methyl 2-propenylpropane dicarboxylic acid diethyl ester, 123 g of potassium hydroxide and 625 ml of ethyl alcohol is heated at reflux for 53 hours. The reaction is cooled, concentrated in vacuo and the residue partitioned between water and diethyl ether. The aqueous layer is separated, made acidic with concentrated hydrochloric acid, saturated with solid sodium chloride and extracted with diethyl ether. The combined diethyl ether layers are dried and concentrated in vacuo to give 80 g of methyl 2-propenylpropane dicarboxylic acid as colorless crystals; MP 89°-90° C.

Twenty three grams of methyl 2-propenylpropane dicarboxylic acid is heated in a Kugelrohr apparatus at 170° C. (20 mm/Hg). Sixteen grams of colorless liquid is collected in an ice cooled receiver. Distillation of the liquid gave racemic 2-methyl-4-pentenoic acid as a colorless liquid; bp 115°-125° C. at 20 mm Hg.

To a solution of 25 g of racemic 2-methyl-4-pentenoic acid, 0.3 g of dimethylformamide and 150 ml of methylene chloride is added, dropwise, 48.2 ml of oxalyl chloride. The resulting solution is stirred at room temperature until gas evolution ceases (3 hours). The reaction is concentrated in vacuo, diluted with methylene chloride and reconcentrated in vacuo to give 29.5 g of crude racemic 2-methyl-4-pentenoyl chloride.

To a 0° C. solution of 23.8 g of benzyl alcohol, 0.05 g of 4-(dimethylamino)pyridine, 18.3 g of pyridine and 250 ml of methylene chloride is added, dropwise, a solution of 29.5 g of racemic 2-methyl-4-pentenoyl chloride in 50 ml of methylene chloride. The mixture is stirred at room temperature for 4 hours, followed by successive washing with 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation to give 35.2 g of the desired product as a colorless oil; bp 70°-75° C. at 0.10 mm Hg.

EXAMPLE 19 Racemic 1-[4-(1-Dimethylamino)-2-butynyl]-3-methyl-2-pyrrolidinone

A stream of ozone is passed through a -78° C. solution of 1.0 g of racemic 2-methyl-4-pentenoic acid phenylmethyl ester in 110 ml of methyl alcohol until the blue color persists. The excess ozone is discharged by a stream of oxygen, followed by argon. One gram of zinc dust and 1.0 g of acetic acid is added and the resulting mixture allowed to warm to room temperature; followed by stirring for 1 hour. The excess zinc is removed by filtration and the filtrate is concentrated in vacuo. The residue is extracted with diethyl ether, filtered and the filtrate concentrated in vacuo. The residue is purified by pad filtration (silica gel, 50% diethyl ether/petroletum ether) to give 1.01 g of racemic 2-methyl-4-oxobutanoic acid phenylmethyl ester.

A solution of racemic 2-methyl-4-oxo-butanoic acid phenylmethyl ester in 5 ml of methyl alcohol is added to a room temperature solution of 3.0 g of N,N-dimethyl-2-butyne-1,4-diamine dihydrochloride, 2.5 g of sodium acetate and 30 ml of methyl alcohol. The resulting solution is stirred at room temperature for 15 minutes. One gram of sodium cyanoborohydride is added, in portions, over 2 hours and the resulting mixture is stirred for 18 hours. The reaction is made acidic with 1.0 ml of concentrated hydrochloric acid and concentrated in vacuo. The residue is made basic with sodium hydroxide and extracted with methylene chloride. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 25-100% ethyl acetate/petroleum ether) to give 5.7 g of the desired product as a pale yellow oil.

CI-MS:m/z 195 (M+H⁺).

Following the general procedure of Example 19, the products of Examples 20-22, found in Table IV, are prepared.

                                      TABLE IV                                     __________________________________________________________________________                                  [alpha].sub.D.sup.26                                   Starting                (methylene chloride)                              Example                                                                             Material #                                                                           Reactant                                                                            Product      or CI-MS: m/z                                     __________________________________________________________________________     20   18    4    Racemic 1-[4-(1-                                                                            223 (M+H.sup.+)                                                   Diethylamino)-2-butynyl]-                                                      3-methyl-2-pyrrolidinone                                       21   16    3    (S)-1-[4-(Dimethylamino)-                                                                   -21°                                                       2-butynyl]-3-methyl-2-                                                         pyrrolidinone                                                  22   17    3    (R)-1-[4-(Dimethylamino)-                                                                   +22°                                                       2-butynyl]-3-methyl-2-                                                         pyrrolidinone                                                  __________________________________________________________________________

EXAMPLE 23 (S)-1-(4-Bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone

A mixture of 3.0 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidine, 0.9 g of paraformaldehyde, 2.5 ml of diethylamine, 3.5 ml of acetic acid and 0.050 g of cuprous chloride is stirred at room temperature for 15 minutes, followed by heating at reflux temperature for 30 minutes. The reaction is cooled, concentrated in vacuo, made basic (pH 10) with ammonium hydroxide and partitioned between methylene chloride and water. The layers are separated, the aqueous layer reextracted and the methylene chloride extracts are combined. The organic solution is dried and concentrated in vacuo with 100 ml of toluene as co-solvent. the residue is purified by chromatography (alumina, activity grade 2.5, 1-5% methyl alcohol/methylene chloride) to give 3.0 g of (S)-1-[4-(diethylamino)-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsily]oxy]-2-pyrrolidinone as a yellow oil.

[α]_(D) ²⁶ =-56 (methylene chloride).

A solution of 2.4 g of (S)-1-[4-diethylamino-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone and 0.8 g of cyanogen bromide in 40 ml of diethyl ether is stirred at room temperature for 18 hours. The solution is washed with 30 ml of 1N hydrochloric acid and saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, methylene chloride) to give 2.0 g of the desired product as a colorless oil.

[α]_(D) ²⁶ =-31° (methylene chloride).

The starting (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidinone is prepared by the procedure described in U.S. Pat. No. 4,937,235.

EXAMPLE 24 (R)-1-(4-Bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone

The title compound is prepared by the procedure of Example 23 using 10.7 g of (R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidinone, 8.7 ml of diethylamine, 3.2 g of paraformaldehyde, 0.10 g of cuprous chloride, 15 ml of lo acetic acid and 100 ml of dioxane. Ten grams of the diamine intermediate is treated with 3.5 g of cyanogen bromide in 150 ml of diethyl ether to give 2.05 g of the desired compound as a yellow oil.

[α]_(D) ²⁶ =+26° (methylene chloride).

The starting (R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidinone is prepared by the procedure described in U.S. Pat. No. 4,937,235.

EXAMPLE 25 1-(4-Bromo-2-butynyl-3-methyl)-2-pyrrolidine

To 31.0 g of N,N-diethyl-2-butyne-1,4-diamine dihydrochloride dissolved in 150 ml of methyl alcohol is added 30 ml of acetic acid and 23.8 g of sodium acetate. The resulting suspension is stirred at room temperature for 20 minutes. Ten grams of 2-methyl-4-oxo-butanoic acid phenylmethyl ester (intermediate in Example 19), is added and the mixture is stirred for 15 minutes. Three grams of sodium cyanoborohydride is added in portions and the mixture is stirred at room temperature for 18 hours.

The reaction mixture is concentrated in vacuo, made basic (pH 12) with 5N sodium hydroxide and extracted with methylene chloride. The combined organic layers are dried, filtered and concentrated in vacuo to give 9.7 g of oil. The oil is purified by chromatography (alumina, activity grade 2.5, 0-75% ethyl acetate/petroleum ether) to give 5.9 g of 1-[4-(diethylamino)-2-butynyl]-3-methyl-2-pyrrolidinone.

CI-MS:m/z 223 (M+H).

A solution of 2.7 g of cyanogen bromide in 50 ml of diethyl ether is added to 5.1 g of 1-[4-(diethylamino)-2-butynyl]-3-methyl-2-pyrrolidinone dissolved in 50 ml diethyl ether. The reaction is stirred at room temperature for 66 hours. The mixture is washed with 1N hydrochloric acid and saturated sodium bicarbonate, dried, filtered and concentrated in vacuo to give 7.1 g of a light yellow oil. The oil is purified by chromatography (silica gel, petroleum ether/ethyl acetate) to give 3.8 g of the desired product.

CI-MS:m/z 247(M+NH₄ ⁺).

EXAMPLE 26 (S)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-[4-(1H-imidazol-1-yl)-2-butynyl]-2-pyrrolidinone

A solution of 2.0 g of (S)-1-(4-bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone, 1.3 g of imidazole and 50 ml of tetrahydrofuran is stirred at room temperature for 72 hours. The solution is concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 2% methyl alcohol/methylene chloride) to give 1.6 g of the desired product as a colorless oil.

[α]_(D) ²⁶ =-30° (methylene chloride)

EXAMPLE 27 (S)-3-Hydroxy-1-[4(1H-imidazol-1-yl)-2-butynyl]-2-pyrrolidinone

A solution of 1.6 g of 1-(4-bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone in 15 ml of 1N methanolic hydrogen chloride is stirred at room temperature for 2 hours. The reaction is concentrated in vacuo, partitioned between methylene chloride and saturated sodium carbonate and the layers are separated. The organic layer is dried and concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 2% methyl alcohol/methylene chloride) to give 0.9 g of the desired product as off-white crystal.

MP 127°-128° C.

[α]_(D) ²⁶ =-47°.(methylene chloride).

Following the general procedure of Examples 26 and 27, the products of Examples 28-33 found in Table V are prepared.

                                      TABLE V                                      __________________________________________________________________________          Starting                 [alpha].sub.D.sup.26                             Example                                                                             Material #                                                                           Reactant                                                                             Product      (methylene chloride)                             __________________________________________________________________________     28   23    Azetidine                                                                            (S)-1-[4-(1-Azetidinyl)-                                                                    -34°                                                       2-butynyl]-3-[[(1,1-                                                           dimethylethyl)-                                                                dimethylsilyl]oxy]-2-                                                          pyrrolidinone                                                 29   24    Imidazole                                                                            (R)-3-[[(1,1-                                                                               +32°                                                       Dimethylethyl)-                                                                dimethylsilyl]oxy]-1-                                                          [4-(1H-imidazol-1-yl)-2-                                                       butynyl]-2-pyrrolidinone                                      30   24    Azetidine                                                                            (R)-1-[4-(1-Azetidinyl)-2-                                                                  +36°                                                       butynyl]-3-[[(1,1-dimethyl-                                                    ethyl)dimethylsilyl]oxy]-2-                                                    pyrrolidinone                                                 31   28    Methanolic                                                                           (S)-3-Hydroxy-1-[4-(1-                                                                      (not stable)                                                hydrogen                                                                             azetidinyl)-2-butynyl]-2-                                                chloride                                                                             pyrrolidinone                                                 32   29    Methanolic                                                                           1-[4-(1H-Imidazol-1-yl)-2-                                                                  +39°                                                 hydrogen                                                                             butynyl]-3-hydroxy-2-                                                    chloride                                                                             pyrrolidinone                                                 33   30    Methanolic                                                                           (R)-3-Hydroxy-1-[4-(1-                                                                      (not stable)                                                hydrogen                                                                             azetidinyl)-2-butynyl]-                                                  chloride                                                                             2-pyrrolidinone                                               __________________________________________________________________________

Examples 34-49 (Table VI) are prepared according to the procedures described in U.S. Pat. No. 4,937,235. An alternate synthetic pathway to the products in Examples 34-49 can be achieved using the process described in Examples 23 and 24.

                                      TABLE VI                                     __________________________________________________________________________          Starting                      [alpha].sub.D.sup.26 or                     Example                                                                             Material #                                                                           Reactant                                                                               Product         CI-MS: m/z                                  __________________________________________________________________________     34   23    Dimethylamine                                                                          (S)-1-[4-(Dimethylamino)-                                                                      -37° (mc)                                               2-butynyl]-3-[[(1,1-                                                           dimethylethyl)-                                                                dimethylsilyl]oxy]-                                                            2-pyrrolidinone                                             35   24    Dimethylamine                                                                          (R)-1-[4-(Dimethylamino)-                                                                      ND                                                             2-butynyl]-3-[[(1,1-                                                           dimethylethyl)dimethyl-                                                        silyl]oxy]-2-pyrro-                                                            lidinone                                                    36   34    Methanolic                                                                             (S)-1-[4-(Dimethylamino)-2-                                                                    -71° (mc)                                       hydrogen                                                                               butynyl]-3-hydroxy-2-                                                  chloride                                                                               pyrrolidinone                                               37   35    Methanolic                                                                             (R)-1-[4-Dimethylamino)-2-                                                                     +69° (mc)                                       hydrogen                                                                               butynyl-3-hydroxy-2-                                                   chloride                                                                               pyrrolidinone                                               38   23    Pyrrolidine                                                                            (S)-3-[[(1,1-Dimethylethyl)-                                                                   -35° (mc)                                               dimethylsily]0xy]-1-[4-(1-                                                     pyrrolidinyl)-2-butynyl]-2-                                                    pyrrolidinone                                               39   24    Pyrrolidine                                                                            (R)-3-[[(1,1-Dimethylethyl)-                                                                   ND                                                             dimethylsilyl]oxy]-1-[4-(1-                                                    pyrrolidinyl)-2-butynyl]-2-                                                    pyrrolidinone                                               40   23    Methanolic                                                                             (S)-3-Hydroxy-1-[4-                                                                            -63° (ma)                                       hydrogen                                                                               (1-pyrrolidinyl)-2-                                                    chloride                                                                               butynyl]-2-pyrrolidinone                                    41   24    Methanolic                                                                             (R)-3-Hydroxy-1-[4-                                                                            +60° (ma)                                       hydrogen                                                                               (1-pyrrolidinyl)-2-                                                    chloride                                                                               butynyl]-2-pyrrolidinone                                    42   23    Methyl- (S)-3-[[(1,1-Dimethylethyl)di-                                                                 ND                                                     aminoethanol                                                                           methylsilyl]oxy]-1-[4-[(2-                                                                     (intermediate)                                                 hydroxyethyl)methylamino]-2-                                                   butynyl]-2-pyrrolidinone                                    43   42    Methanolic                                                                             (S)-3-Hydroxy-1-[4-                                                                            -38° (ma)                                       hydrogen                                                                               [(2-hydroxyethyl)                                                      chloride                                                                               methylamino]-2-butynyl]-2-                                                     pyrrolidinone                                               44   24    Methylamino                                                                            (S)-3-[[(1,1-Dimethylethyl)di-                                                                 ND                                                     butanol methylsilyl]oxy]-1-[4-[(4-                                                                     (intermediate)                                                 hydroxybutyl)methylamino]-2-                                                   butynyl]-2-pyrrolidinone                                    45   44    Methanolic                                                                             (R)-3-Hydroxy-1-[4-                                                                            +33° (ma)                                       hydrogen                                                                               [(4-hydroxybutyl)methylamino]-                                         chloride                                                                               2-butynyl]-2-pyrrolidinone                                  46   25    Imidazole                                                                              Racemic 1-[4-(1H-imidazol-1-                                                                   218 (M+H.sup.+)                                                yl)-2-butynyl]-3-methyl-2-                                                     pyrrolidinone                                               47   25    Azetidine                                                                              Racemic 1-[4-(1-                                                                               207 (M+H.sup.+)                                                azetidinyl)-2-butynyl]-3-                                                      methyl-2-pyrrolidinone                                      48   25    (S)-3[[(1,1-                                                                           [R-[(R*,R* and R*,S*)]]-                                                                       365 (M+H.sup.+)                                        Dimethyl-                                                                              1-[4-[2-[[[(1,1-dimethyl-                                              ethyl)di-                                                                              ethyl)dimethylsilyl]oxy]                                               methylsilyl]-                                                                          methyl]-1-pyrrolidinyl]-2-                                             oxy]methyl]-                                                                           butynyl]-3-methyl-2-pyrro-                                             1-pyrroli-                                                                             lidinone                                                               dinone                                                              49   25    (S)-3-[[(1,1-                                                                          [R-(R*,R* and R*,S*)]-1-                                                                       -2° (mc)                                        dimethylethyl)-                                                                        [4-[3[[(1,1-dimethylethyl)-                                                                    351 (M+H.sup.+)                                        dimethylsilyl]-                                                                        dimethylsilyl]oxy]-1-pyrro-                                            1-pyrrolidine                                                                          lidinyl-2-butynyl]-3-methyl-2-                                         carboxylic acid                                                                        pyrrolidinone                                                          phenyl methyl                                                                  ester                                                               __________________________________________________________________________      ND = Not done                                                                  (mc) = Rotation done in methylene chloride                                     (ma) = Rotation done in methyl alcohol                                   

EXAMPLE 50 (S)-2-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinecarboxylic acid phenylmethyl ester

To a 0° C. solution of 25 g of (S)-2-pyrrolidinemethanol in 150 ml of diethyl ether is added 54.8 g of benzyl chloroformate. At mid point of addition, 49.4 ml of 5N sodium hydroxide is added, simultaneously, and the reaction stirred at 0° C. for 2 hours. Diethyl ether is added, the layers are separated and the aqueous layer reextracted with diethyl ether. The combined organic layers are dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel, 0-10% methyl alcohol/methylene chloride) to give 59.1 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester.

A solution 58.0 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester, 45.0 g of (1,1-dimethylethyl)dimethylsilylchloride, 69 ml of triethylamine, 1.50 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride is stirred at room temperature for 18 hours. The resulting solution is washed with water, 2N hydrochloric acid, saturated sodium bicarbonate and sodium chloride. The organic layer is dried and concentrated in vacuo. The residue, dissolved in methylene chloride, is filtered through a silica gel pad and concentrated in vacuo to give 76.5 g of the desired product as a colorless oil.

[α]_(D) ²⁶ =-46 (methylene chloride).

EXAMPLE 51 (R)-2-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinecaboxylic acid phenylmethyl ester

The title compound is prepared by the procedure of Example 50 using 20.0 g of (R)-2-pyrrolidinemethanol, 44.0 g of benzyl chloroformate and 200 ml of diethyl ether to give 56.4 g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenyl methyl ester. Forty-five g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester is reacted with 38.4 g of (1,1-dimethylethyl)dimethylsilylchloride, 58 ml of triethylamine, 1.3 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride to give 41.5 g of the desired product as a colorless oil.

[α]_(D) ²⁶ =+45° (methylene chloride).

EXAMPLE 52 (S)-3-(Acetoxy)-1-(2-propynyl)-2-pyrrolidinone

A solution of 4.3 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 10.6 ml of acetic anhydride, 0.6 ml of pyridine, 0.1 g of 4-(dimethylamino)pyridine and 85 ml of methylene chloride is stirred at room temperature for 18 hours. Twenty-five ml of methyl alcohol is added and the reaction stirred for 20 minutes. The mixture is washed with 1N hydrochloric acid and saturated sodium bicarbonate. The organic layer is dried, passed thorough a pad of hydrous magnesium silicate and concentrated in vacuo to give 4.9 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =+60° (methylene chloride).

EXAMPLE 53 (R)-3-(Acetoxy)-1-(2-propynyl)-2-pyrrolidinone

The title compound is prepared by the procedure of Example 52 using 19.6 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 26.6 ml of acetic anhydride, 17 ml of pyridine, 0.6 g of 4-(dimethylamino)pyridine and 200 ml of methylene chloride to give 23.4 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =+59° (methylene chloride).

EXAMPLE 54 [R-(R*,S*)]-3-(Acetoxy)-1-[4-[2-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-1]-2-pyrrolidinone

A mixture of 7.3 g of (S)-3[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidine carboxylic acid phenylmethyl ester, 0.40 g of 10% palladium on carbon and 225 ml of ethyl alcohol is hydrogenated in a Parr apparatus at room temperature under atmospheric pressure. The catalyst is removed by filtration, the filtrate is diluted with 100 ml of toluene and concentrated in vacuo. The residue is treated with 2.4 g of product from Example 53, 0.65 g of paraformaldehyde, 0.38 g of cuprous chloride, 1.8 ml of acetic acid and 75 ml of dioxane. The resulting mixture is heated at reflux temperature for 45 minutes, cooled, made basic with ammonium hydroxide and extracted with methylene chloride. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 1% methyl alcohol/methylene chloride) to give 3.6 g of the desired product as an orange/red oil.

[α]_(D) ²⁶ =-4° (methyl alcohol)

Following the general procedure for Example 54, the products of Examples 55-61, found in Table VII, are prepared.

                                      TABLE VII                                    __________________________________________________________________________          Starting                       [alpha].sub.D.sup.26                       Example                                                                             Material #                                                                           Reactant                                                                               Product          (methyl alcohol)                           __________________________________________________________________________     55   52    50      [S-(R*,R*)]-3-(Acetyloxy)-1-                                                                    -56°                                                   [4-[2-[[[(1,1-dimethylethyl)-                                                  dimethylsilyl]oxy]methyl]-                                                     1-pyrrolidinyl]-2-butynyl]-2-                                                  pyrrolidinone                                               56   52    51      [S-(R*,S*)]-3-(Acetyloxy)-1-                                                                     -4°                                                   [4-(2-[[[(1,1-dimethylethyl)                                                   dimethylsilyl]oxy]methyl]-                                                     1-pyrrolidinyl]-2-butynyl]-2-                                                  pyrrolidinone                                               57   53    51      [R-(R*,R*)]-3-Acetyloxy)-1-                                                                     +53°                                                   [4-[2-[[[(1,1-dimethylethyl)-                                                  dimethylsilyl]oxy]methyl]-                                                     1-pyrrolidinyl]-2-butynyl]-2-                                                  pyrrolidinone                                               58   52    2-      (S)-3-(Acetyloxy)-1-[4-[2-                                                                      -45°                                           (Methylamino)                                                                          (hydroxyethyl)methylamino]-2-                                          ethanol butynyl]-2-pyrrolidinone                                    59   53    2-      (R)-3-(Acetyloxy)-1-[4-[2-                                                                      +45°                                           (Methylamino)                                                                          (hydroxyethyl)methylamino]-2-                                          ethanol butynyl]-2-pyrrolidinone                                    60   52    2-      (S)-3-(Acetyloxy)-1-[4-[(4-hydroxy-                                                             -43°                                           (Methylamino)                                                                          butyl)methylamino]-2-butynyl]-2-                                       butanol pyrrolidinone                                               61   53    2-      (R)-3-(Acetyloxy)-1-[4-[(4-hydroxy-                                                             +43°                                           (Methylamino)                                                                          butyl)methylamino]-2-butynyl]-2-                                       butanol pyrrolidinone                                               __________________________________________________________________________

EXAMPLE 62 [R-(R*,S*)]-1-[4-[2-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinyl]-2-butynyl]-3-hydroxy-2-pyrrolidone

A solution of 0.90 g of product from Example 54, 1.4 g of potassium carbonate and 25 ml of methyl alcohol is stirred at room temperature for 4 hours. The solution is passed through a pad of diatomaceous earth and the filtrate concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 10% methyl alcohol/methylene chloride) to give 0.42 g of the desired product as a red/orange oil.

[α]_(D) ²⁶ =-15° (methyl alcohol).

Following the general procedure of Example 62, the products of Examples 63-69, found in Table VIII, are prepared.

                                      TABLE VIII                                   __________________________________________________________________________          Starting                    [alpha].sub.D.sup.26                          Example                                                                             Material #                                                                           Reactant                                                                             Product         (methyl alcohol)                              __________________________________________________________________________     63   55    Potassium                                                                            [S-(R*,R*)]-1-[4-[2-[[[(1,1-                                                                   -59°                                              carbonate                                                                            Dimethylethyl)dimethylsilyl]-                                                  oxy]methyl]-1-pyrrolidinyl]-                                                   2-butynyl]-3-hydroxy-2-                                                        pyrrolidinone                                                 64   56    Potassium                                                                            [S-(R*,S*)]-1-[4-[2-[[[(1,1-                                                                    +7°                                              carbonate                                                                            Dimethylethyl)dimethylsilyl]-                                                  oxy]methyl]-1-pyrrolidinyl]-                                                   2-butynyl]-3-hydroxy-2-                                                        pyrrolidinone                                                 65   57    Potassium                                                                            [R-(R*,R*)]-1-[4-[2-[[[(1,1-                                                                   +46°                                              carbonate                                                                            Dimethylethyl)dimethylsilyl]-                                                  oxy]methyl]-1-pyrrolidinyl]-                                                   2-butynyl]-3-hydroxy-2-                                                        pyrrolidinone                                                 .sup. 66.sup.a                                                                      58    Potassium                                                                            (S)-3-Hydroxy-1-[4-[(2-hydroxy-                                                                -38°                                              carbonate                                                                            ethyl)methylamino]-2-butynyl]-2-                                               pyrrolidinone                                                 67   59    Potassium                                                                            (R)-3-Hydroxy-1-[4-[(2-hydroxy-                                                                +36°                                              carbonate                                                                            ethyl)methylamino]-2-butynyl]-2-                                               pyrrolidinone                                                 68   60    Potassium                                                                            (S)-3-Hydroxy-1-[4-[(4-                                                                        -35°                                              carbonate                                                                            hydroxybutyl)methylamino]-2-                                                   butynyl]-2-pyrrolidinone                                      .sup. 69.sup.b                                                                      61    Potassium                                                                            (R)-3-Hydroxy-1-[4-[(4-                                                                        +33°                                              carbonate                                                                            hydroxybutyl)methylamino]-2-                                                   butynyl]-2-pyrrolidinone                                      __________________________________________________________________________      .sup.a Same product as Example 43.                                             .sup.b Same product as Example 45.                                       

EXAMPLE 70 [S-(R*,S*)]-3-Hydroxy-1-[4-[2-(hydroxymethyl)-1-pyrrolidinyl]-2-butynyl]-2-pyrrolidinone

A solution of 1.62 g of product from Example 64, 35 ml of,methyl alcohol and 2.1 ml of concentrated hydrochloric acid is stirred at room temperature for 4 hours. The solution is concentrated in vacuo and the residue is partitioned between 10N sodium hydroxide and methylene chloride. The organic layer is dried and concentrated in vacuo. The residue is purified by pad filtration (alumina, 10% methyl alcohol/methylene chloride) to give 0.910 g of the desired product as a viscous yellow oil.

[α]_(D) ²⁶ =+2° (methyl alcohol).

Following the general procedure of Example 70, the products of Examples 71 & 72, found in Table IX, are prepared.

                                      TABLE IX                                     __________________________________________________________________________          Starting                                                                  Example                                                                             Material #                                                                           Reactant                                                                              Product      [alpha].sub.D.sup.26                            __________________________________________________________________________     71   63    Hydrochloric                                                                          [S-(R*,R*)]-3-Hydroxy-1-                                                                    -73°                                                acid   [4-[2-(hydroxymethyl)-1-                                                                    (methyl alcohol)                                                  pyrrolidinyl]-2-butynyl]-2-                                                    pyrrolidinone                                                72   62    Hydrochloric                                                                          [R-(R*,S*)]-3-Hydroxy-1-                                                                    ND                                                         acid   [4-[2-(hydroxymethyl)-1-                                                       pyrrolidinyl]-2-butynyl]-2-                                                    pyrrolidinone                                                __________________________________________________________________________      ND = Not done                                                            

EXAMPLE 73 (S)-3-(Methylthio)-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone

A solution of 1.2 g of (S)-3-thio-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone in 100 ml of methylene chloride is added to a stirred suspension of 31 g of activated silica gel in 100 ml of methylene chloride. The mixture is stirred for 15 minutes to ensure absorption of the thiol on the silica gel. Two hundred and twenty ml of 0.4M diethyl ether solution of diazomethane is added in portions over 30 minutes. The solution is filtered and the silica gel washed thoroughly with methyl alcohol. The filtrate is concentrated in vacuo and the residue purified by chromatography (alumina, activity grade 2.5, 1% methyl alcohol/methylene chloride) to give 0.275 g of the desired product as a red/orange oil.

[α]_(D) ²⁶ =-49° (methyl alcohol).

Following the general procedure of Example 73, the products of Examples 74-77, found in Table X, are prepared.

                                      TABLE X                                      __________________________________________________________________________          Starting                     [alpha].sub.D.sup.26                         Example                                                                             Material #                                                                             Reactant                                                                               Product      (methyl alcohol)                             __________________________________________________________________________     74   (R)-3-Thio-1-                                                                          Diazomethane                                                                           (R)-3-(Methylthio)-1-[4-(1-                                                                 +40°                                       [4-(1-          pyrrolidinyl)-2-butynyl]-2-                                    pyrrolidinyl)-  pyrrolidinone                                                  2-butynyl-2-                                                                   pyrrolidinone                                                             75   (S)-3-Thio-1-                                                                          Diazomethane                                                                           (S)-1-[4-(Dimethylamino)-                                                                   -53°                                       [4-(1-dimethyl- 2-butynyl]-3-(methylthio)-                                     amino)-2-       2-pyrrolidinone                                                butynyl]-2-                                                                    pyrrolidinone                                                             76   (R)-3-Thio-1-                                                                          Diazomethane                                                                           (R)-1-[4-(Dimethylamino)-                                                                   +45°                                       [4-(1-dimethyl- 2-butynyl]-3-(methylthio)-                                     amino)-2-       2-pyrrolidinone                                                butynyl]-2-                                                                    pyrrolidinone                                                             77   75      Methyl  (S)-N,N, N-Trimethyl-4-[3-                                                                  +31°                                               iodide  (methylthio)-2-oxo1-                                                           pyrrolidinyl]-2-butyn-1-                                                       aminium iodide                                            __________________________________________________________________________

EXAMPLE 78 (S)-3-Azido-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone

A solution of 0.75 ml of methanesulfonyl chloride in 5 ml of methylene chloride is added, dropwise, to a 0° C. solution of 1.0 g of product from Example 46, 1.5 ml of triethylamine and 25 ml of methylene chloride. The mixture is stirred at 0° C. for 1 1/2hours. The reaction is diluted with methylene chloride and saturated sodium carbonate. The organic layer is washed with saturated sodium chloride, dried, diluted with toluene and concentrated in vacuo. The resulting 1.2 g of the methanesulfonate is used without further purification.

A solution of 1.2 g of the methanesulfonate, 1.4 g of sodium azide and 25 ml of methyl alcohol is stirred at room temperature for 18 hours; followed by heating at reflux temperature for 1.5 hours. The reaction is cooled, diluted with diethyl ether and filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo and the residue partitioned between water and methylene chloride. The organic layer is dried, concentrated in vacuo, and the residue is purified by chromatography (alumina; activity grade 2.5, 1% methyl alcohol/methylene chloride) to give 0.88 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =-175°

EXAMPLE 79 (S)-3-Amino-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone dihydrochloride

A mixture of 0.70 g of product from Example 78, 9.5 g of zinc dust and 10 ml of acetic acid is stirred at room temperature for 1.5 hours. The reaction is filtered, the zinc is washed with methylene chloride and the filtrate concentrated in vacuo. The residue is partitioned between methylene chloride and 6 ml of ammonium hydroxide. The organic layer is dried and concentrated in vacuo. The residue is dissolved in 1N methanolic hydrogen chloride and diluted with diethyl ether. The resulting precipitate is collected and recrystallized from ethyl alcohol/diethyl ether to give 0.24 g of the desired product as colorless crystals.

MP 224°-226° C.

[α]_(D) ²⁶ =-29° (methyl alcohol).

Following the general procedure of Example 79, the products of Examples 80-87, found in Table XI, are prepared.

                                      TABLE XI                                     __________________________________________________________________________          Starting                  MP °C. or [alpha].sub.D.sup.26           Example                                                                             Material #                                                                               Reactant                                                                            Product    (methyl alcohol)                                __________________________________________________________________________     80   (R)-3-Hydroxy-1-                                                                         Sodium                                                                              (R)-3-Azido-1-[4-(1-                                                                      +190°                                         [4-(1-pyrrolidinyl)-                                                                     azide                                                                               pyrrolidinyl)-                                                  2-butynyl]-2-  2-butynyl]-2-                                                   pyrrolidinone  pyrrolidinone                                              81   (S)-3-Hydroxy-1-                                                                         Sodium                                                                              (S)-3-Azido-1-[4-                                                                         -188°                                         [4-(1-dimethyl-                                                                          azide                                                                               (dimethylamino)-2-                                              amino)-2-butynyl]-                                                                            butynyl]-2-pyrro-                                               2-pyrrolidinone                                                                               lidinone                                                   82   (R)-3-Hydroxy-1-                                                                         Sodium                                                                              (R)-3-Azido-1-[4-                                                                         +185°                                         [4-(1-dimethyl-                                                                          azide                                                                               (dimethylamino)-2-                                              amino)-2-butynyl]-                                                                            butynyl]-2-pyrro-                                               2-pyrrolidinone                                                                               lidinone                                                   83   81        Methyl                                                                              (S)-4-(3-Azido-2-oxo-                                                                     -122°                                                   iodide                                                                              1-pyrrolidinyl)-N,N,                                                           N-trimethyl-2-butyn-1-                                                         aminium iodide                                             84   82        Methyl                                                                              (R)-4-(3-Azido-2-oxo-                                                                     +103°                                                   iodide                                                                              1-pyrrolidinyl)-N,N,                                                           N-trimethyl-2-butyn-1-                                                         aminium iodide                                             85   80        Zinc/                                                                               (R)-3-Amino-1-[4-(1-                                                                       -30°                                                   acetic                                                                              pyrrolidinyl)-2-                                                          acid butynyl]-2-pyrro-                                                              lidinone dihydro-                                                              chloride                                                   86   81        Zinc/                                                                               (S)-3-Amino-1-[4-                                                                          -33°                                                   acetic                                                                              (dimethylamino)-2-                                                        acid butynyl]-2-pyrro-                                                              lidinone dihydro-                                                              chloride                                                   87   82        Zinc/                                                                               (R)-3-Amino-1-[4-                                                                          +32°                                                   acetic                                                                              (dimethylamino)-2-                                                        acid butynyl]-2-pyrro-                                                              lidinone dihydro-                                                              chloride                                                   __________________________________________________________________________

EXAMPLE 88 (S)-2-Methylpropanoic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester

A solution of 0.84 g of isobutyryl chloride in 15 ml of methylene chloride is added, dropwise, to a 0° C. solution of 1.4 g of (S)-3-hydroxy-1-[4-(1-dimethylamino)-2-butynyl]-2-pyrrolidinone, 3 ml of triethylamine, 0.10 g of 4-(dimethylamino)pyridine and 25 ml methylene chloride. The mixture is stirred at room temperature for 18 hours. Two ml of methyl alcohol is added and the methylene chloride solution is washed with 1N hydrochloric acid and saturated sodium carbonate, dried and concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 1% methyl alcohol/methylene chloride) to give 1.65 g of the desired product as a pale yellow oil.

[α]_(D) ²⁶ =-44° (methylene chloride).

Following the general procedure of Example 88, the products of Examples 89-124, found in Table XII, are prepared.

                                      TABLE XII                                    __________________________________________________________________________          Starting                      MP °C. or [alpha].sub.D.sup.26       Example                                                                             Material #                                                                             Reactant                                                                              Product        (methyl alcohol)                            __________________________________________________________________________     89   37      2,2-Dimethyl-                                                                         (S)-2,2-Dimethylpropanoic                                                                     -39°                                              propanoyl                                                                             acid 1-[4-(dimethylamino)-                                              chloride                                                                              2-butynyl]-2-oxo-3-pyrro-                                                      lidinyl ester                                              90   37      Decanoyl                                                                              (S)-Decanoic acid 1-[4-                                                                       -36°                                              chloride                                                                              (dimethylamino)2-butynyl]-                                                     2-oxo-3-pyrrolidinyl ester                                 91   37      Octyl  (S)-Carbonic acid 1-[4-                                                                       -40°                                              chloro-                                                                               (dimethylamino)-2-butynyl]-                                             formate                                                                               2-oxo-3-pyrrolidinyl octyl ester                           92   37      Methyl (S)-Carbonic acid 1-[4-                                                                       -60°                                              chloro-                                                                               (dimethylamino)-2-butynyl]-                                             formate                                                                               2-oxo-3-pyrrolidinyl methyl                                                    ester                                                      93   90      Methyl (S)-N,N, N-Trimethyl-4-[2-oxo-                                                                -28°                                              iodide 3-[(1-oxodecyl)oxy]-1-pyrro-                                                   lidinyl-2-butyn-1-aminium                                                      iodide                                                     94   88      Methyl (S)-N,N, N-Trimethyl-4-[3-                                                                    -35°                                              iodide (2-methyl-1-oxopropoxy)-                                                       2-oxo-1-pyrrolidinyl]-                                                         2-butyn-1-aminium iodide                                   95   89      Methyl (S)-4-[3-(2,2-Dimethyl-1-                                                                     -33°                                              iodide oxopropoxy)-2-oxo-1-pyrro-                                                     lidinyl]-N,N, N-trimethyl-                                                     2-butyn-1-aminium iodide                                   96   91      Methyl (S)-N,N, N-Trimethyl-4-[3-                                                                    -33°                                              iodide [[(octyloxy)carbonyl]oxy]-                                                     2-oxo-1-pyrrolidinyl]-                                                         2-butyn-1-aminium iodide                                   97   40      Isobutyryl                                                                            (S)-2-Methylpropanoic acid                                                                    -42°                                              chloride                                                                              2-oxo-1-[4-(1-pyrrolidinyl)-                                                   2-butynyl]-3-pyrrolidinyl                                                      ester                                                      98   40      Pivaloyl                                                                              (S)-2,2-Dimethylpropanoic                                                                     -37°                                              chloride                                                                              acid 2-oxo-1-[4-(1-pyrro-                                                      lidinyl)-2-butynyl]-3-                                                         pyrrolidinyl ester                                         99   40      Methyl (S)-3-[[Methylamino)car-                                                                      -39°                                              isocyanate                                                                            bonyl]oxy]-1-[4-(1-pyrro-                                                      lidinyl)-2-butynyl]-2-                                                         pyrrolidinone                                              100  40      Dimethyl-                                                                             (S)-Dimethylcarbamic acid                                                                     -33°                                              carbamoyl                                                                             2-oxo-1-[4-(1-pyrrolidinyl)-                                            chloride                                                                              2-butynyl]-3-pyrrolidinyl                                                      ester                                                      101  40      Hexyl  (S)-Carbonic acid hexyl 2-                                                                    -43°                                              chloro-                                                                               oxo-1-[4-(1-pyrrolidinyl)-                                              formate                                                                               2-butynyl]-3-pyrrolidinyl                                                      ester                                                      102  40      t-Butyl                                                                               (S)-Carbonic acid 1,1-di-                                                                     -46°                                              chloro-                                                                               methylethyl-2-oxo-1-[4-                                                 formate                                                                               (1-pyrrolidinyl)-2-butynyl]-                                                   3-pyrrolidinyl ester                                       103  40      Methyl (S)-Carbonic acid methyl 2-                                                                   -56°                                              chloro-                                                                               oxo-1-[4-(1-pyrrolidinyl)-2-                                            formate                                                                               butynyl]-3-pyrrolidinyl ester                              104  36      Isobutyryl                                                                            (R)-Porpanoic acid 2-                                                                         +44°                                              chloride                                                                              methyl-1-[4-(dimethyl-                                                         amino)-2-butynyl]-2-oxo-                                                       3-pyrrolidinyl ester                                       105  36      Pivaloyl                                                                              (R)-2,2-Dimethylpropanoic                                                                     +38°                                              chloride                                                                              acid 1-[4-(dimethylamino)-                                                     2-butynyl]-2-oxo-3-pyrro-                                                      lidinyl ester                                              106  36      Decanoyl                                                                              (R)-Decanoic acid 1-[4-                                                                       +35°                                              chloride                                                                              (dimethylamino)-2-butynyl]-                                                    2-oxo-3-pyrrolidinyl ester                                 107  36      Decanoyl                                                                              (R)-Octylcarbamic acid 1-[4-                                                                  +28°                                              chloride                                                                              (dimethylamino)-2-butynyl]-                                                    2-oxo-2-pyrrolidinyl ester                                 108  36      Methyl (R)-Carbonic acid 1-[4-                                                                       +61°                                              chloro-                                                                               (dimethylamino)-2-butynyl]-                                             formate                                                                               2-oxo-3-pyrrolidinyl methyl                                                    ester monohydrochloride                                    109  36      Octyl  (R)-Carbonic acid 1-[4-                                                                       +36°                                              chloro-                                                                               (dimethylamino)-2-butynyl]-                                             formate                                                                               2-oxo-3-pyrrolidinyl octyl                                                     ester                                                      110  104     Methyl (R)-N,N, N-Trimethyl-4-[3-(2-                                                                 +35°                                              iodide methyl-1-oxopropoxy)-2-oxo-                                                                   MP 128-130°                                              1-pyrrolidinyl]-2-butyn-1                                                      aminium iodide                                             111  105     Methyl (R)-3-[3-(2,2-Dimethyl-1-                                                                     +32°                                              iodide oxopropoxy)-2-oxo-1-pyrro-                                                                    MP 160-162°                                              lidinyl]-N,N, N-trimethyl-                                                     2-butyn-1-aminium iodide                                   112  106     Methyl (R)-4-[2-Oxo-3-[(1-oxodecyl)-                                                                 +28°                                              iodide oxy]-1-pyrrolidinyl]-N,N, N-                                                                  MP 103-105°                                              trimethyl-2-butyn-1-aminium                                                    iodide                                                     113  107     Methyl (R)-N,N, N-Trimethyl-4-[3-                                                                    +34°                                              iodide [[(octylamino)carbonyl]oxy]-                                                   2-oxo-1-pyrrolidinyl]-2-butyn-                                                 1-aminium iodide                                           114  109     Methyl (R)-N,N, N-Trimethyl-4-[3-                                                                    +34°                                              iodide [[(octyloxy)carbonyl]oxy]-                                                     2-oxo-1-pyrrolidinyl]-2-                                                       butyn-1-aminium iodide                                     115  41      Isobutyryl                                                                            (R)-2-Methylpropanoic acid                                                                    +42°                                              chloride                                                                              2-oxo-1-[4-(1-pyrrolidinyl)-                                                   2-butynyl]-3-pyrrolidinyl                                                      ester                                                      116  41      Pivaloyl                                                                              (R)-2,2-Dimethylpropanoic                                                                     +37°                                              chloride                                                                              acid 2-oxo-1-[4-(1-pyrro-                                                      lidinyl)-2-butynyl]-3-                                                         pyrrolidinyl ester                                         117  41      Decanoyl                                                                              (R)-Decanoic acid 2-oxo-1-                                                                    +35°                                              chloride                                                                              [4-(1-pyrrolidinyl)-2-butynyl]-                                                3-pyrrolidinyl ester                                       118  41      Benzyl (R)-Carbonic acid 2-oxo-1-                                                                    +38°                                              chloro-                                                                               [4-(1-pyrrolidinyl)-2-                                                  formate                                                                               butynyl]-3-pyrrolidinyl                                                        phenylmethyl ester                                         119  41      Octyl  (R)-Octylcarbamic acid 2-                                                                     +28°                                              isocyanate                                                                            oxo-1-[4-(1-pyrrolidinyl)-                                                                    MP 47-49°                                                2-butynyl]-3-pyrrolidinyl                                                      ester                                                      120  41      Octyl  (R)-Carbonic acid octyl 2-                                                                    +39°                                              chloro-                                                                               oxo-1-[4-(1-pyrrolidinyl)-2-                                            formate                                                                               butynyl]-3-pyrrolidinyl ester                              121  41      Methyl (R)-Carbonic acid methyl 2-                                                                   +56°                                              chloro-                                                                               oxo-1-[4-(1-pyrrolidinyl)-2-                                            formate                                                                               butynyl]-3-pyrrolidinyl ester                              122  (S)-4-Hydroxy-                                                                         Decanoyl                                                                              (S)-Decanoic acid 2-oxo-1-[4-                                                                 -36°                                      1-[4-(1-                                                                               chloride                                                                              (1-pyrrolidinyl)-2-butynyl]-4-                                  pyrrolidinyl)- pyrrolidinyl ester                                              2-butynyl]-2-                                                                  pyrrolidinone                                                             123  (S)-4-Hydroxy-                                                                         Methyl (S)-Carbonic acid methyl                                                                       -5°                                      1-[4-(1-pyrro-                                                                         chloro-                                                                               2-oxo-1-[4-(1-pyrro-                                            lidinyl)-2-                                                                            form-  lidinyl)-2-butynyl]-4-pyrro-                                    butynyl]-2-                                                                            ate    lidinyl ester                                                   pyrrolidinone                                                             124  (S)-4-Hydroxy-                                                                         Octyl  (S)-Octylcarbamic acid                                                                         +6°                                      1-[4-(1-pyrro-                                                                         iso-   2-oxo-1-[4-(1-pyrrolidinyl)-                                    lidinyl)-2-                                                                            cyan-  2-butynyl]-4-pyrrolidinyl                                       butynyl-2-                                                                             ate    ester                                                           pyrrolidinone                                                             __________________________________________________________________________

Following the general procedure of Example 88, the Examples 125-Example 163, found in Table XIII, are prepared.

                                      TABLE XIII                                   __________________________________________________________________________          Starting                           Optical                                     Material   Procedure               Rotation                               Example                                                                             Example    of                      [α].sub.25°.sup.D         No.  No.  Reagent                                                                              Example #                                                                            Name of Product   (MeOH)                                 __________________________________________________________________________     125  36   Butyryl                                                                              88    (S)-Butanoic acid 1-[4-                                                                          -45°                                      chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       126  36   Hexanoyl                                                                             88    (S)-Hexanoic acid 1-[4-                                                                          -42°                                      chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       127  36   Octanoyl                                                                             88    (S)-Octanoic acid 1-[4-                                                                          -34°                                      chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       128  36   Ethyl 88    (S)-Ethylcarbamic acid 1-[4-                                                                     -35°                                      isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       129  36   Butyl 88    (S)-Butylcarbamic acid 1-[4-                                                                     -26°                                      isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       130  36   Hexyl 88    (S)-Hexylcarbamic acid 1-[4-                                                                     -31°                                      isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       131  36   Octyl 88    (S)-Octylcarbamic acid 1-[4-                                                                     -19°                                      isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       132  36   Ethyl 88    (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                             -55°                                      chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                 formate     ethyl ester                                              133  36   Butyl 88    (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                             -52°                                      chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                 formate     butyl ester                                              134  36   Hexyl 88    (S)-1-[4-(Dimethylamino)-2-butynyl]-                                                             -46°                                      chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                 formate     hexyl ester                                              135  37   Butyrl                                                                               88    (R)-Butanoic acid 1-[4-                                                                          +47°                                      chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       136  37   Hexanoyl                                                                             88    (R)-Hexanoic acid 1-[4-                                                                          +41°                                      chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       137  37   Octanoyl                                                                             88    (R)-Octanoic acid 1-[4-                                                                          +40°                                      chloride    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       138  37   Ethyl 88    (R)-Ethylcarbamic acid 1-[4-                                                                     +33°                                      isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       139  37   Butyl 88    (R)-Butylcarbamic acid 1-[4-                                                                     +36°                                      isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       140  37   Hexyl 88    (R)-Hexylcarbamic acid 1-[4-                                                                     +27°                                      isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       141  37   Ethyl 88    (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                             +57°                                      chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                 formate     ethyl ester                                              142  37   Butyl 88    (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                             +53°                                      Chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                 formate     butyl ester                                              143  37   Hexyl 88    (R)-1-[4-(Dimethylamino)-2-butynyl]-                                                             +45°                                      chloro-     2-oxo-3-pyrrolidinyl carbonic acid                                 formate     hexyl ester                                              144  40   Butyryl                                                                              88    (S)-Butanoic acid 2-oxo-1-[4-(1-                                                                 -43°                                      chloride    pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       145  40   Hexanoyl                                                                             88    (S)-Hexanoic acid 2-oxo-1-[4-(1-                                                                 -39°                                      chloride    pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       146  40   Octanoyl                                                                             88    (S)-Octanoic acid 1-[4-(1-                                                                       -37°                                      chloride    pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       147  40   Decanoyl                                                                             88    (S)-Decanoic acid 2-oxo-1-[4-(1-                                                                 -36°                                      chloride    pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       148  40   Ethyl 88    (S)-Ethylcarbamic acid 2-oxo-1-[4-(1-                                                            -30°                                      isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       149  40   Butyl 88    (S)-Butylcarbamic acid 1-2-oxo-[4-(1-                                                            -29°                                      isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       150  40   Hexyl 88    (S)-Hexylcarbamic acid 2-oxo-1-[4-(1-                                                            -26°                                      isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       151  40   Octyl 88    (S)-Octylcarbamic acid 2-oxo-1-[4-(1-                                                            -27°                                      isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       152  40   Ethyl 88    (S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                               -52.sup.                                         chloro-     butynyl]-3-pyrrolidinyl carbonic acid                              formate     ethyl ester                                              153  40   Butyl 88    (S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                               -48°                                      chloro-     butynyl]-3-pyrrolidinyl carbonic acid                              formate     butyl ester                                              154  40   Octyl 88    (S)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                               -40°                                      chloro-     butynyl]-3-pyrrolidinyl carbonic acid                              formate     octyl ester                                              155  41   Butyrl                                                                               88    (R)-Butanoic acid 2-oxo-1-[4-(1-                                                                 +40°                                      chloride    pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       156  41   Hexanoyl                                                                             88    (R)-Hexanoic acid 2-oxo-1-[4-(1-                                                                 +41°                                      chloride    pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       157  41   Octanoyl                                                                             88    (R)-Octanoic acid 2-oxo-1-[4-(1-                                                                 +40°                                      chloride    pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       158  41   Ethyl 88    (R)-Ethylcarbamic acid 2-oxo-1-[4-(1-                                                            +30°                                      isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       159  41   Butyl 88    (R)-Butylcarbamic acid 2-oxo-1-[4-(1-                                                            +27°                                      isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       160  41   Hexyl 88    (R)-Hexylcarbamic acid 2-oxo-1-[4-(1-                                                            +28°                                      isocyanate  pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl ester                                       161  41   Ethyl 88    (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                               +52°                                      chloro-     butynyl]-3-pyrrolidinyl carbonic acid                              formate     ethyl ester                                              162  41   Butyl 88    (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                               +45°                                      chloro-     butynyl]-3-pyrrolidinyl carbonic acid                              formate     butyl ester                                              163  41   Hexyl 88    (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                                               +41°                                      chloro-     butynyl]-3-pyrrolidinyl carbonic acid                              formate     hexyl ester                                              __________________________________________________________________________

EXAMPLE 164 (R)-3-(Dimethylamino)-1-[4-(1-pyrrolidinyl-2-butynyl]-2-pyrrolidinone

Following the procedure of Example 78, a solution of 0.5 g of the methanesulfonate of the product from Example 40 and 0.5 g (excess) dimethylamine in 25 ml of methylene chloride is stirred at room temperature overnight. The reaction is concentrated at reduced pressure and the residue is purified by column chromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5% (v/v) gradient methylene chloride/methanol) to give the product.

EXAMPLE 165 (S)-3-(Dimethylamino)-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone

A solution of 0.5 g of the product from Example 79 , 0.2 g of paraformaldehyde (excess) and 1 ml of acetic acid in 10 ml of methanol is stirred at room temperature for 15 minutes. Portionwise, 0.5 g of sodium cyanoborohydride, is added over 30 minutes. The resulting mixture is stirred at room temperature for 1 hour and concentrated at reduced pressure. The residue is basified with saturated aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue is purified by column chromatography (Al₂ O₃, Activity Grade 2.5; methylene chloride to 1-5% (v/v) gradient methylene chloride/methanol) to give the product.

EXAMPLE 166 (R)N-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl]acetamide

A solution of 0.2 g of acetyl chloride in 5 ml of methylene chloride is added, dropwise, to a stirring 0° C. solution of 0.5 g of the product from Example 85 and 0.3 g of triethylamine in 10 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred overnight. The reaction is washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate and concentrated at reduce temperature to dryness. The residue is purified by column chromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5% (v/v) gradient methylene chloride/methanol) to give the product.

EXAMPLE 167 Cyclopentanecarbonyl chloride

A solution of 1.0 g of oxalyl chloride in 15 ml of methylene chloride is added, dropwise, to a 0° C. solution of 0.5 g of cyclopentane carboxylic acid in 15 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred for 6 hours. The solution is concentrated at reduced pressure, rediluted with 25 ml of methylene chloride and reconcentrated to give the corresponding acid chloride of cyclopentane carboxylic acid.

EXAMPLE 168 (R) N-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl]cyclopentanecarboxamide

A solution of the product from Example 167 in 15 ml of methylene chloride is added, dropwise, to a 0° C. solution of 0.5 g of the product from,Example 85 and 0.3 g of triethylamine in 10 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred overnight. The reaction is washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue is purified by column chromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5% (v/v) gradient methylene chloride/methanol) to give the produce.

The following Examples 169-184, found in Table XIV, are prepared in an analogous manner. In the following examples: Reagent B, a carboxylic acid, is reacted by Procedure C, the resulting acid chloride intermediate is then reacted with the starting material A following the procedure C' to give product D. For example, in Example 169, cyclopentylacetic acid is reacted by the procedure of Example 167. The intermediate formed, cyclopentylcarbonyl chloride, is reacted with the starting material from Example 41 using the procedure of Example 168 to give the desired product.

                                      TABLE XIV                                    __________________________________________________________________________          Starting                                                                       Material     Procedure                                                    Example                                                                             Example                                                                             Reagent of Example                                                                           Name of Product                                        No   No. (A)                                                                             (B)     (C)  (C')                                                                            (D)                                                    __________________________________________________________________________     169  41   cyclopentyl-                                                                           167, 168                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               acetic acid   butynyl]-3-pyrrolidinyl cyclopentyl-                                           acetamide                                              170  41   cyclohexyl-                                                                            167, 168                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               acetic acid   butynyl]-3-pyrrolidinyl cyclohexyl-                                            acetamide                                              171  41   3-tetrahydro-                                                                          167, 168                                                                             Tetrahydro-N-[2-oxo-1-[4-(1-                                     furoic acid   pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl]-3-furancarboxamide                       172  40   [(S)-   167, 168                                                                             [S-(R*, R*)]-1-Methyl-N-[2-oxo-1-[4-(1-                          1-methyl-     pyrrolidinyl)-2-butynyl]-3-                                      pyroline]     pyrrolidinyl]-2-pyrrolidine-carboxamide                173  41   4-Cyano-                                                                               166   (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               benzoyl       butynyl]-3-pyrrolidinyl-4-cyanobenzamide               174  41   2-Bromophenyl                                                                          167, 168                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               acetic acid   butynyl]-3-pyrrolidinyl 2-bromophenyl-                                         acetamide                                              175  41   4-Methoxy-                                                                             167, 168                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               phenyl acetic butynyl]-2-oxo-3-pyrrolidinyl 4-                                 acid          methoxyphenyl-acetamide                                176  41   2-Furoyl                                                                               166   (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             chloride      butynyl]-3-pyrrolidinyl 2-furan-                                               carboxamide                                            177  41   nicotinyl                                                                              166   (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             chloride      butynyl]-3-pyrrolidinyl 3-pyridine-                                            carboxamide                                            178  41   isonicotinyl                                                                           166   (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             chloride      butynyl]-3-pyrrolidinyl 4-pyridine-                                            carboxamide                                            179  41   3-thiophene                                                                            167, 168                                                                             (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             carboxylic    butynyl]-3-pyrrolidinyl 3-thiophene-                             acid          carboxamide,                                           180  41   2-thiophene-                                                                           167, 168                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               acetic acid   butynyl]-3-pyrrolidinyl 2-thiophene-                                           acetamide                                              181  41   3-thiophene-                                                                           167, 168                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               acetic acid   butynyl]-3-pyrrolidinyl 3-thiophene-                                           acetamide                                              182  41   1-methyl-                                                                              167, 168                                                                             (R)-1-Methyl-N-[2-oxo-1-[4-(1-                                   imidazole-4-  pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                          acetic acid   1H-imidazole-4-carboxamide                             183  41   4-pyridine-                                                                            167, 168                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                               acetic acid   butynyl]-3-pyrrolidinyl 4-pyridine-                                            acetamide                                              184  41   3-pyridine-                                                                            167, 168                                                                             (R)-N-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             acetic acid   butynyl]-3-pyrrolidinyl 3-pyridine-                                            acetamide                                              __________________________________________________________________________

EXAMPLE 185 Cyclopentyl chloroformate

A solution of 0.543 g of cyclopentyl alcohol in 15 ml of methylene chloride is added to a 0° C. solution of 1.0 ml of a 10% toluene solution of phosgene in toluene in 10 ml of methylene chloride. The reaction is allowed to warm to room temperature and is stirred for 3 hours. The reaction is concentrated at reduced pressure, diluted with 15 ml of toluene and reconcentrated to dryness to give the product.

EXAMPLE 186 (R) [2-Oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl]carbamic acid, cyclopentylmethyl ester

Following the procedure of Example 168 and using the products from Examples 85 and Example 185 the titled product is prepared.

The following Examples 187-198, found in Table XV, are prepared in an analogous manner.

                                      TABLE XV                                     __________________________________________________________________________          Starting       Prodedure                                                       Material       of                                                         Example                                                                             Example        Example                                                    No   No   Reagent   No    Name of Product                                      __________________________________________________________________________     187  41   cycloheptane                                                                             185, 186                                                                             (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                               methanol        butynyl]-3-pyrrolidinylcarbamic acid                 188  41   cyclohexane                                                                              185, 186                                                                             (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                               methanol        butynyl]-3-pyrrolidinylcarbamic acid                                           cyclohexylmethyl ester                               189  41   tetrahydro-4H-                                                                           185, 186                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             pyran-4-ol      butynyl]-3-pyrrolidinylcarbamic acid                                           tetrahydro-2H-pyran-4-yl ester                       190  41   tetrahydro-3-                                                                            185, 186                                                                             2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                 furanemethanol  butynyl]-3-pyrrolidinylcarbamic acid                                           (tetrahydro-3-furanyl)methyl ester                   191  41   4-methoxyphenyl                                                                          88, 91                                                                               (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                               chloroformate   butynyl]-3-pyrrolidinyl-carbamic acid                                          4-methoxyphenyl ester                                192  41   benzyl    88, 91                                                                               (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                               chloroformate   butynyl]-3-pyrrolidinylcarbamic acid                                           phenylmethyl ester                                   193  41   4-chlorobenzyl                                                                           88, 91                                                                               (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             chloroformate   butynyl]-3-pyrrolidinylcarbamic acid                                           (4-chlorophenyl)methyl ester                         194  41   2-        185, 186                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             thiophenemethanol                                                                              butynyl]-3-pyrrolidinylcarbamic acid                                           3-thienylmethyl ester                                195  41   2-(2-thienyl)                                                                            185, 186                                                                             (R)-2-Oxo-1-[4-(pyrrolidinyl)-2-                               ethanol         butynyl]-3-pyrrolidinyl carbamic acid                                          2-(2-thienyl)ethyl ester                             196  41   2-(3-thienyl)                                                                            185, 186                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             ethanol         butynyl]-3-pyrrolidinylcarbamic acid 2-                                        (3-thienyl)ethyl ester                               197  41   2-(2-pyridyl)                                                                            185, 186                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             ethanol         butynyl]-3-pyrrolidinylcarbamic acid                                           2-(2-pyridinyl)ethyl ester                           198  41   2-(6-methyl-2-                                                                           185, 186                                                                             (R)-2-Oxo-1-[4-(1-pyrrolidinyl)-2-                             pyridyl)ethanol butynyl]-3-pyrrolidinylcarbamic acid                                           2-(6-methyl-2-pyridinyl)ethyl                        __________________________________________________________________________                               ester                                           

EXAMPLE 199 (R)-1-(2-propynyl)-3-(methoxymethoxy)-2-pyrrolidinone

A solution of 1.0 g of chloromethyl methyl ether in 15 ml of methylene chloride is added dropwise to a solution of 1.5 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidione, prepared by the procedure of Example 1, U.S. Pat. No. 5,089,518, and 1.5 g of ethyldiisopropylamine in 15 ml of methylene chloride which is stirred in an ice bath. The reaction is allowed to warm to room temperature and stirred overnight. The solution was washed with water, aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The methylene chloride solution is concentrated at reduced pressure and purified by column chromatography (silica gel: mehylene chloride) to give the product.

EXAMPLE 200 (R)-1-[4-(Dimethylamino)-2-butynyl]-3-(methoxymethoxy)-2-pyrrolidinone

A solution of 2.2 g of product from 199, 0.93 g of dimethylamine, 0.8 g of paraformaldehyde, 1.0 g of acetic acid, 0.050 g of cuprous chloride in 50 ml of dioxane is stirred at room temperature for two days. The mixture is cooled and concentrated at reduced pressure. The residue is basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, and concentrated at reduced pressure to dryness. The residue is purified (Alumina, Activity Grade 2.5: ethyl acetate/hexane 1:1 (v/v)) to give the product.

The following Examples 201-209, found in Table XVI, are prepared in an analogous manner.

                                      TABLE XVI                                    __________________________________________________________________________          Starting                                                                       Material                                                                  Example                                                                             Example      Procedure of                                                 No.  No.  Reagent Example #                                                                             Name of Product                                       __________________________________________________________________________     201  37   chloromethyl                                                                           199, 200                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-                            ethyl ether    3-(ethoxymethoxy)-2-pyrrolidinone                     202  37   chloromethyl                                                                           199, 200                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-                            isobutyl ether 3-[(2-methoylpropoxy)methoxy]-2-                                               pyrrolidinone                                         203  37   chloromethyl                                                                           199, 200                                                                              (R)-3-(Butoxymethoxy)-1-[4-                                     butyl ether    (dimethylamino)-2-butynyl]-2-                                                  pyrrolidinone                                         204  37   chloromethyl                                                                           199, 200                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-                            octyl ether    3-(octyloxymethoxy)-2-pyrrolidinone                   205  37   trimethylsilyl-                                                                        199, 200                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-                            ethoxy methyl- 3-[[2-(trimethylsily)-                                          chloride       ethoxy]methoxy]-2-pyrrolidinone                       206  37   alpha, 4-                                                                              199, 200                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-                            dichloroanisole                                                                               3-[(4-chlorophenoxy)methoxy]-2-                                                pyrrolidinone                                         207  37   benzyl chloro-                                                                         199, 200                                                                              (R)-1-[4-(1-Dimethylamino)-2-                                   methyl ether   butynyl]-3-[(phenylmethoxy)methoxy]-                                           2-pyrrolidinone                                       208  37   chloromethyl                                                                           199, 200                                                                              (R)-2,2-Dimethylpropanoic acid, [[1-                            pivalate       [4-(dimethylamino)-2-butynyl]-2-oxo-                                           3-pyrrolidinyl]oxy]methyl ester                       209  37   chloromethyl                                                                           199, 200                                                                              (R)-3-[(Benzoyloxy)methoxy]-1-[4-                               benzoate       (dimethylamino)-2-butynyl]-2-                                                  pyrrolidinone                                         __________________________________________________________________________

EXAMPLE 210 Cyclopentanecarbonyl chloride

A solution of 1.0 g of oxalylchloride in 15 ml of methylene chloride is added dropwise to a 0° C. solution of 0.5 g of cyclopentane carboxylic acid in 15 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred for 6 hours. The solution is concentrated at reduced pressure, rediluted with 25 ml of methylene chloride and reconcentrated to give the product.

EXAMPLE 211 (S)-Cyclopentanecarboxylic acid 2-oxo-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinyl ester

A solution of cyclopentanecarbonyl chloride from Example 210 in 15 ml of methylene chloride is added dropwise to a 0° C. solution of 0.5 g of produce from Example 85, 86 or 87 and 0.3 g of triethylamine in 10 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred overnight. The reaction is washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue is purified by column chromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5% (v/v) gradient methylene chloride/methanol) to give the product.

The following Examples 212-250, found in Table XVII, are prepared in an analogous manner.

                                      TABLE XVII                                   __________________________________________________________________________                        Procedure                                                        Starting      of                                                          Example                                                                             Material      Example                                                     No.  No.  Reagent  No.   Name of Product                                       __________________________________________________________________________     212  40   cyclobutane                                                                             210, 211                                                                             (S)-Cyclobutanecarboxylic acid 2-oxo-1-                         carboxylic acid                                                                               [4-(1-pyrrolidinyl)-2-butynyl-3-                                               pyrrolidinyl ester                                    213  40   cyclopentane                                                                            210, 211                                                                             (S)-Cylopentanecarboxylic acid 2-oxo-1-                         carboxylic acid                                                                               [4-(1-pyrrolidinyl)-2-butynyl]-3-                                              pyrrolidinyl ester                                    214  40   N-methyl-L-                                                                             210, 211                                                                             [(S)(R*,R*)]-1-Methyl-2-pyrrolidinyl-                           proline        carboxylic acid 2-oxo-1-[4-(1-                                                 pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                        ester                                                 215  40   3-       210, 211                                                                             (S)-3-tetrahydrofuroic acid 2-oxo-1-[4-                         tetrahydrofuroic                                                                              (1-pyrrolidinyl)-2-butynyl]-3-                                  acid           pyrrolidinyl ester                                    216  37   naphthoyl                                                                               88    (S)-Naphthoic acid 1-[4-(dimethylamino)-                        chloride       2-butynyl]-2-oxo-3-pyrrolidinyl ester                 217  36   4-biphenyl                                                                              88    (S)-4-Biphenylcarboxylic acid 1-[4-                             carbonyl chloride                                                                             (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                    218  36   benzoyl  88    (S)-Benzoic acid 1-[4-(dimethylamino)-2-                        chloride       butynyl]-2-oxo-3-pyrrolidinyl ester                   219  36   2-fluorobenzoyl                                                                         88    (S)-2-Fluorobenzoic acid 1-[4-                                  chloride       (dimetylamino)-2-butynyl]-2-oxo-3-                                             pyrrolidinyl ester                                    220  36   3-chlorobenzoyl                                                                         88    (S)-3-Chlorobenzoic acid 1-[4-                                  chloride       (dimetylamino)-2-butynyl]-2-oxo-3-                                             pyrrolidinyl ester                                    221  36   4-bromobenzoyl                                                                          88    (S)-4-Bromobenzoic acid 1-[4-                                   chloride       (dimetylamino)-2-butynyl]-2-oxo-3-                                             pyrrolidinyl ester                                    222  36   2-Iodobenzoyl                                                                           88    (S)-2-Iodobenzoic acid 1-[4-                                    chloride       (dimetylamino)-2-butynyl]-2-oxo-3-                                             pyrrolidinyl ester                                    223  36   3-cyanobenzoyl                                                                          88    (S)-3-Cyanobenzoic acid 1-[4-                                   chloride       (dimetylamino)-2-butynyl]-2-oxo-3-                                             pyrrolidinyl ester                                    224  36   4-nitrobenzoyl                                                                          88    (S)-4-Nitrobenzoic acid 1-[4-                                   chloride       (dimetylamino)-2-butynyl]-2-oxo-3-                                             pyrrolidinyl ester                                    225  36   p-anisoyl                                                                               88    (S)-4-Methoxybenzoic acid 1-[4-                                 chloride       (dimetylamino)-2-butynyl]-2-oxo-3-                                             pyrrolidinyl ester                                    226  40   4-fluorophenyl                                                                          167, 88                                                                              (S)-4-Fluorophenylacetic acid 2-oxo-1-                          acetic acid    [4-(1-pyrrolidinyl)-2-butynyl]-3-                                              pyrrolidinyl ester                                    227  40   4-methoxyphenyl                                                                         167, 88                                                                              (S)-4-Methoxyphenylacetic acid 2-oxo-1-                         acetic acid    [4-(1-pyrrolidinyl)-2-butynyl]-3-                                              pyrrolidinyl ester                                    228  40   iso-nicotinoyl                                                                          88    (S)-3-Pyridinecarboxylic acid 2-oxo-1-                          chloride       [4-(1-pyrrolidinyl)-2-butynyl]-3-                                              pyrrolidinyl ester                                    229  40   2-furoyl chloride                                                                       88    (S)-2-Furancarboxylic acid 2-oxo-1-[4-                                         (1-pyrrolidiyl)-2-butynyl]-3-                                                  pyrrolidinyl ester                                    230  40   5-methyl-2-                                                                             210, 211                                                                             (S)-5-Methyl-2-pyrazinecarboxylic acid                          pyrazine       2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-                         carboxylic acid                                                                               3-pyrrolidinyl ester                                  231  40   nicotinoyl                                                                              88    (S)-3-Pyridinecarboxylic acid, 2-oxo-1-                         chloride       [4-(1-pyrrolidinyl)-2-butynyl]-3-                                              pyrrolidinyl ester                                    232  40   2-pyridylacetic                                                                         210, 211                                                                             (S)-2-PYridylacetic acid 2-oxo-1-[4-(1-                         acid           pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                        ester                                                 233  40   1-methyl-2-                                                                             210, 211                                                                             (S)-1-Methyl-1H-pyrrole-2-carboxylic                            pyrroleacetic  acid, 2-oxo-1-[4-(1-pyrrolidinyl)-2-                            acid           butynyl]-3-pyrrolidinyl ester                         234  40   2-thiopheneacetic                                                                       210, 211                                                                             (S)-2-Thiopheneacetic acid 2-oxo-1-[4-                          acid           (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                    235  40   3-thiopheneacetic                                                                       210, 211                                                                             (S)-3-Thiopheneacetic acid 2-oxo-1-[4-                          acid           (1-pyrrolidinyl)-2-butynyl]-3-                                                 pyrrolidinyl ester                                    236  40   1-methyl-                                                                               210, 211                                                                             (S)-1-Methyl-1H-imidazole-4-carboxylic                          imidazole-4-   acid, 2-oxo-1-[4-(1-pyrrolidinyl)-2-                            acetic acid    butynyl]-3-pyrrolidinyl ester                         237  40   4-pyridylacetic                                                                         210, 211                                                                             (S)-4-Pyridylacetic acid 2-oxo-1-[4-(1-                         acid           pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                        ester                                                 238  40   3-pyridylacetic                                                                         210, 211                                                                             (S)-3-Pyridylacetic acid 2-oxo-1-[4-(1-                         acid           pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                        ester                                                 239  40   butyryl chloride                                                                        88    (S)-Butanoic acid 2-oxo-1-[4-(1-                                               pyrrolidinyl)-2-butynyl]-3-pyrrolidinyl                                        ester                                                 240  37   cyclopentyl                                                                             88    (R)-Cyclopentylcarbonic acid 1-[4-                              chloroformate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                    241  37   cyclohexyl                                                                              88    (R)-Cyclohexylcarbonic acid 1-[4-                               chloroformate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                    242  37   cyclopentane-                                                                           185, 88                                                                              (R) Cyclopentylmethylcarbonic acid, 1-                          methanol       [4-(dimethylamino)-2-butynyl]-2-oxo-3-                                         pyrrolidinyl ester                                    243  37   tetrahydro-4H-                                                                          185, 88                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                          pyran-4-ol     oxo-3-pyrrolidinylcarbonic acid,                                               tetrahydro-2H-pyran-4-yl ester                        244  37   tetrahydro-3-                                                                           185, 88                                                                              1-[4-(Dimethylamino)-2-butynyl]-2-oxo-3-                        furanemethanol pyrrolidinylcarbonic acid, (tetrahydro-                                        3-furanyl)methyl ester                                245  37   4-bromophenyl                                                                           88    (R)-4-Bromophenyl-1-[4-(dimethylamino)-                         chloroformate  2-butynyl]-2-oxo-3-pyrrolidinylcarbonic                                        acid ester                                            246  37   benzyl   88    (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                          chloroformate  oxo-3-pyrrolidinylcarbonic acid                                                phenylmethyl ester                                    247  37   2-thiophene                                                                             185, 88                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                          methanol       oxo-3-pyrrolidinylcarbonic acid,                                               2-thienylmethyl ester                                 248  37   2-(2-thienyl)                                                                           185, 88                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                          ethanol        oxo-3-pyrrolidinylcarbonic acid, 2-(2-                                         thienyl)ethyl ester                                   249  37   2-(3-thienyl)                                                                           185, 88                                                                              (R)-1-[4-(Dimethylamino)-2-butynyl]-2-                          ethanol        oxo-3-pyrrolidinylcarbonic acid, 2-(2-                                         thienyl)ethyl ester                                   250  36   2-(3-thienyl)                                                                           185, ,88                                                                             (S)-1-[4-(Dimethylamino)-2-butynyl]-2-                          ethanol        oxo-3-pyrrolidinylcarbonic acid, 2-(2-                                         thienyl)ethyl ester                                   __________________________________________________________________________

The following Examples 251-252, found in Table XVIII, are prepared by the procedure of Example 88 and 119.

                                      TABLE XVIII                                  __________________________________________________________________________                     Procedure                                                           Starting   of                                                             Example                                                                             Material   Example                                                        No.  No.  Reagent                                                                              No.   Name of Product                                          __________________________________________________________________________     251  36   cyclopentyl                                                                          88 119                                                                               (S)-Cyclopentylcarbamic acid 1-[4-                                 isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       252  36   cyclohexyl                                                                           88 119                                                                               (S)-Cyclohexylcarbamic acid 1-[4-                                  isocyanate  (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                       __________________________________________________________________________

EXAMPLE 253 3-Cyclopentylpropionyl chloride

A solution of 1.0 g of oxalyl chloride in 15 ml of methylene chloride is added dropwise to a 0° C. solution of 0.65 g of 3-cyclopentylpropionic acid in 15 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred for 6 hours. The solution is concentrated at reduced pressure, rediluted with 25 ml of methylene chloride and reconcentrated to give 3-cyclopentylpropionyl chloride.

EXAMPLE 254 2-Cyclopentylethyl isocyanate

The procedure is an adaptation of procedure in Org. Syn. Col. Vol II, p 846, Col. VI, p 95. A solution of 0.65 g of 3-cyclopentylpropionyl chloride (Example 253) in 10 ml of acetone is added dropwise to a 0° C. solution of 0.46 g of sodium azide in 5 ml of water When the addition is complete, stirring is continued for 1 hour. The mixture is extracted wink toluene, dried over anhydrous sodium sulfate and filtered. The toluene solution is added dropwise to 25 ml of toluene which is heated at reflux temperature. When the addition is complete, the reaction is refluxed until nitrogen evolution has ceased (ca 1 hour). The reaction is cooled and the resulting toluene solution of the corresponding isocyanate is then used a% in Example 124, 119, 99, and all new examples.

The following Examples 255-269, found in Table XIX, are prepared by the procedure of Example 88 and 119.

                                      TABLE XIX                                    __________________________________________________________________________          Starting       Procedure                                                       Material       of                                                         Example                                                                             Example        Exmaple                                                    No.  No.  Reagent   No.   Name of Product                                      __________________________________________________________________________     255  36   tetrahydro-3-                                                                            253, 254,                                                                            Tetrahydro-3-furanylcarbamic acid, 1-                          furoic acid                                                                              88    [4-dimethylamino)-2-butynyl]-2-oxo-3-                                          pyrrolidinyl ester                                   256  36   1-methyl-L-                                                                              253, 254,                                                                            [S-(R*,R*)] (1-Methyl-2-pyrrolidinyl)-                         pyroline  88    carbamic acid, 1-[4-(dimethylamino)-2-                                         butynyl]-2-oxo-3-pyrrolidinyl ester                  257  36   3-chlorophenyl                                                                           88    (S)-3-Chlorophenylcarbamic acid, 1-[4-                         isocyanate      (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   258  36   benzyl isocyanate                                                                        88    (S)-Phenylmethylcarbamic acid, 1-[4-                                           (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   259  36   phenethyl 88    (S)-(2-Phenylethyl)carbamic acid, 1-[4-                        isocyanate      (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   260  36   3-thiophene                                                                              253, 254,                                                                            (S)-3-Thienylcarbamic acid, 1-[4-                              carboxylic acid                                                                          88    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   261  36   3-thiopheneacetic                                                                        253, 254,                                                                            (S)-3-Thienylmethylcarbamic acid 1-[4-                         acid      88    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   262  36   2-thiopheneacetic                                                                        253, 254,                                                                            (S)-2-Thienylmethylcarbamic acid 1-[4-                         acid      88    (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   263  36   dimethyl  88    (S)-Dimethylcarbamic acid 1-[4-                                carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                            chloride        pyrrolidinyl ester                                   264  36   diethyl carbamoyl                                                                        88    (S)-Diethylcarbamic acid 1-[4-                                 chloride        (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   265  36   N-methyl-N-phenyl                                                                        88    (S)-N-Methyl-N-phenylcarbamic acid 1-[4-                       carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                            chloride        pyrrolidinyl ester                                   266  36   1-pyrrolidine                                                                            88    (S)-1-Pyrrolidinecarboxylic acid 1-[4-                         carbonyl chloride                                                                              (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   267  36   4-morpholine                                                                             88    (S)-4-Morpholinecarboxylic acid 1-[4-                          carbonyl chloride                                                                              (dimethylamino)-2-butynyl]-2-oxo-3-                                            pyrrolidinyl ester                                   268  36   diphenyl  88    (S)-Diphenylcarbamic acid 1-[4-                                carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                            chloride        pyrrolidinyl ester                                   269  37   dibenzyl  88    (S)-Bis(phenylmethyl)carbamic acid 1-[4-                       carbamoyl       (dimethylamino)-2-butynyl]-2-oxo-3-                            chloride        pyrrolidinyl ester                                   __________________________________________________________________________

EXAMPLE 270 (S)-S-[1-[4-Dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl]-cyclopentylmethylthioic acid ester

A solution of product from Example 167 in 15 ml of methylene chloride is added dropwise to a 0° C. solution of 0.5 g of product from Example 68, prepared according to U.S. Pat. No. 5,089,518, and 0.3 g of triethylamine in 10 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred overnight. The reaction is washed with saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue is purified by column chromatography (Al₂ O₃, Activity Grade 2.5: methylene chloride to 1-5% (v/v) methylene chloride/methanol) to give the product.

The following Examples 271-299 found in Table XX, are prepared in an analogous manner.

                                      TABLE XX                                     __________________________________________________________________________          Starting                                                                       Material       Procedure                                                  Example                                                                             Example        of Example                                                 No.  No.  Reagent   No.   Name of Product                                      __________________________________________________________________________     271  41   cyclobutane                                                                              167, 270                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          carboxylic acid butynyl]-3-pyrrolidinyl]                                                       cyclobutanecarbothioic acid ester                    272  41   cyclopentane                                                                             167, 270                                                                             (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          carboxylic acid butynyl]-3-pyrrolidinyl]                                                       cyclopentanecarbothioic acid ester                   273  40   N-methyl-L-proline                                                                       167, 270                                                                             [(S)(R*,R*)]-S-[2-Oxo-1-[4-(1-                                                 pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl] 1-methyl-2-                                                      pyrrolidinylcarbothioic acid ester                   274  41   tetrahydro-3-                                                                            167, 270                                                                             S-Tetrahydro-3-furancarbothioic acid                           furoic acid     [2-oxo-1-[4-(1-pyrrolidinyl)-2-                                                butynyl]-3-pyrrolidinyl ester                        275  41   p-anisic acid                                                                            167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                          butynyl]-3-pyrrolidinyl] 4-methoxy-                                            phenylcarbothioic acid ester                         276  40   p-anisoyl chloride                                                                       88    (S)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                          butynyl]-3-pyrrolidinyl] 4-                                                    methoxyphenylcarbothioic acid ester                  277  41   4-fluorophenyl                                                                           167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          acetic acid     butynyl]-3-pyrrolidinyl] 4-                                                    fluorophenylethanethioic acid ester                  278  41   4-methoxyphenyl                                                                          167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          acetic acid     butynyl]-3-pyrrolidinyl] 4-methoxy-                                            phenylethanethioic acid ester                        279  41   2-furoyl chloride                                                                        88    (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                                          butynyl]-3-pyrrolidinyl] 2-furane-                                             carbothioic acid ester                               280  41   5-methyl-2-                                                                              167, 88                                                                              (R)-5-Methylpyrazinecarbothioic acid,                          pyrazine        S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                              carboxylic acid butynyl]-3-pyrrolidinyl] ester                       281  41   2-pyridylacetic                                                                          167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          acid            butynyl]-3-pyrrolidinyl] pyridine-2-                                           ethanethioic thioic acid ester                       282  41   1-methyl-2-                                                                              167, 88                                                                              (R)-1-Methyl-1H-pyrrole-2-                                     pyrroleacetic acid                                                                             ethanethioic acid, S-[2-oxo-1-[4-(1-                                           pyrrolidinyl)-2-butynyl]-3-                                                    pyrrolidinyl] ester,                                 283  41   2-thiopheneacetic                                                                        167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          acid            butynyl]-3-pyrrolidinyl] thiophene-2-                                          ethanethioic acid ester                              284  41   3-thiopheneacetic                                                                        167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          acid            butynyl]-3-pyrrolidinyl] thiophene-3-                                          ethanethioic acid ester                              285  41   4-pyridineacetic                                                                         167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          acid            butynyl]-3-pyrrolidinyl] pyridine-4-                                           ethanethioic acid ester                              286  41   3-pyridineacetic                                                                         167, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          acid            butynyl]-3-pyrrolidinyl] pyridine-3-                                           ethanethioic acid ester                              287  41   cyclopentyl                                                                              88    (R)-O-Cyclopentylcarbonothioic acid,                           chloroformate   S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                              butynyl]-3-pyrrolidiinyl] ester                      288  41   cyclohexyl                                                                               88    (R)-O-Cyclopentylcarbonothioic acid,                           chloroformate   S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                              butynyl]-3-pyrrolidinyl] ester                       289  41   cyclopentane-                                                                            185, 88                                                                              (R)-O-Cyclopentylmethylcarbonothioic                           methanol        acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-                                          2-butynyl]-3-pyrrolidinyl] ester                     290  41   tetrahydro-4H-                                                                           185, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          pyran-4-ol      butynyl]-3-pyrrolidinyl]carbonothioic                                          acid, O-(tetrahydro-2H-pyran-4-yl)                                             ester                                                291  41   tetrahydro-3-                                                                            185, 88                                                                              S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                              furanemethanol  butynyl]-3-pyrrolidinyl]carbonothioic                                          acid, O-(tetrahydro-3-furanyl)methyl                                           ester                                                292  41   4-bromophenyl                                                                            88    (R)-O-(4-Bromophenyl)carbonothioic                             chloroformate   acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-                                          2-butynyl]-3-pyrrolidinyl] ester                     293  41   benzyl    88    (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          chloroformate   butynyl]-3-pyrrolidinyl]carbonothioic                                          acid, O-(phenylmethyl) ester                         294  41   2-thiophene                                                                              185,88                                                                               (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          methanol        butynyl]-3-pyrrolidinyl]carbonothioic                                          acid, O-(2-thienyl)methyl ester                      295  41   2-(2-thienyl)                                                                            185, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          ethanol         butynyl]-3-pyrrolidinyl]carbonothioic                                          acid, O-[2-(2-thienyl)ethyl] ester                   296  41   3-(3-thienyl)                                                                            185, 88                                                                              (R)-S-[2-Oxo-1-[4-(1-pyrrolidinyl)-2-                          ethanol         butynyl]-3-pyrrolidinyl]carbonothioic                                          acid, O-[2-(3-thienyl)ethyl] ester                   297  41   cyclopentyl                                                                              88    (R)-Cyclopentylcarbamothioic acid,                             isocyanate      S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                              butynyl]-3-pyrrolidinyl] ester                       298  41   cyclohexyl                                                                               88    (R)-Cyclohexylcarbamothioic acid, S-                           isocyanate      [2-oxo-1-[4-(1-pyrrolidinyl)-2-                                                butynyl]-3-pyrrolidinyl] ester                       299  41   tetrahydrofuroic                                                                         253, 254, 88                                                                         (Tetrahydro-3-furanyl)carbamothioic                            acid            acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-                                          2-butynyl]-3-pyrrolidinyl] ester                     __________________________________________________________________________

The following Examples 300-312, found in Table XXI, are prepared by the procedures listed.

                                      TABLE XXI                                    __________________________________________________________________________          Starting                                                                  Starting                                                                            Material       Procedure                                                  Material                                                                            Example        of                                                         No.  No.  Reagent   Example #                                                                            Name of Product                                      __________________________________________________________________________     300  41   p-anisoyl 254, 88                                                                              (R)-4-Methoxyphenylcarbamothioic acid,                         chloride        S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                              butynyl]-3-pyrrolidinyl] ester                       301  41   benzyl    88    (R)-2-Phenylmethylcarbamothioic acid, S-                       isocyanate      [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-                                       3-pyrrolidinyl] ester                                302  41   phenethyl 88    (R)-2-Phenylethylcarbamothioic acid, S-                        isocyanate      [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-                                       3-pyrrolidinyl] ester                                303  41   3-thiophene                                                                              253, 254,                                                                            (R)-3-Thienylcarbamothioic acid, S-[2-                         carboxylic acid                                                                          88    oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                        pyrrolidinyl] ester                                  304  41   3-thiopheneacetic                                                                        253, 254,                                                                            (R)-3-Thienylethanethioic acid, S-[2-                          acid      88    oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                        pyrrolidinyl] ester                                  305  41   2-thiopheneacetic                                                                        253, 254,                                                                            (R)-3-Thienylethanecarbamothioic acid,                         acid      88    S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                              butynyl]-3-pyrrolidinyl] ester                       306  41   dimethyl  88    (R)-N,N-Dimethylcarbamothioic acid, S-                         carbamoyl       [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl-                        chloride        3-pyrrolidinyl] ester                                307  41   diethyl carbamoyl                                                                        88    (R)-N,N-Diethylaminocarbamothioic acid,                        chloride        S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                              butynyl-3-pyrrolidinyl] ester                        308  41   N-methyl-N-phenyl                                                                        88    (R)-N-Methyl-N-phenylcarbamothioic acid,                       carbamoyl       S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                              chloride        butynyl-3-pyrrolidinyl] ester                        309  41   1-pyrrolidine                                                                            88    (R)-1-Pyrrolidinecarbothioic acid, S-                          carbonyl chloride                                                                              [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl-                                        3-pyrrolidinyl] ester                                310  41   4-morpholine                                                                             88    (R)-4-Morpholinecarbothioic acid, S-[2-                        carbonyl chloride                                                                              oxo-1-[4-(1-pyrrolidinyl)-2-butynyl]-3-                                        pyrrolidinyl] ester                                  311  41   diphenyl  88    (R)-N,N-Diphenylcarbamothioic acid, S-                         carbamoyl       [2-oxo-1-[4-(1-pyrrolidinyl)-2-butynyl-                        chloride        3-pyrrolidinyl] ester                                312  41   dibenzylcarbamoyl                                                                        88    (R)-N,N-Bis(phenylmethyl)carbamothioic                         chloride        acid, S-[2-oxo-1-[4-(1-pyrrolidinyl)-2-                                        butynyl-3-pyrrolidinyl] ester                        __________________________________________________________________________

The following Examples 313-317, found in Table XXII, are prepared by the procedures listed.

                                      TABLE XXII                                   __________________________________________________________________________          Starting                                                                       Material    Procedure                                                     Example                                                                             Example     of Example             M.P.                                   No.  No.   Reagent                                                                              #     Name of Product  °C.                             __________________________________________________________________________     313  Example 1                                                                            Ethyl 88    (R)-Ethylcarbamic acid, 2-oxo-1-(2-                                                             85-87                                       U.S. Pat.                                                                            isocyanate  propynyl)-3-pyrrolidinyl ester                               5,089,518                                                                 314  Example 1                                                                            Ethyl 88    (S)-Ethylcarbamic acid, 2-oxo-1-(2-                                                             87-89                                       U.S. Pat.                                                                            isocyanate  propynyl)-3-pyrrolidinyl ester                               5,089,518                                                                 315  Example 1                                                                            Butyl 88    (S)-Butylcarbamic acid, 2-oxo-1-(2-                                                             51-53                                       U.S. Pat.                                                                            isocyanate  propynyl)-3-pyrrolidinyl ester                               5,089,518                                                                 316  Example 1                                                                            Ethyl 88    (S)-Hexylcarbamic acid, 2-oxo-1-(2-                                                             64-66                                       U.S. Pat.                                                                            isocyanate  propynyl)-3-pyrrolidinyl ester                               5,089,518                                                                 317  Example 1                                                                            Ethyl 88    (R)-Octylcarbamic acid, 2-oxo-1-                                                                70-72                                       U.S. Pat.                                                                            isocyanate  (2-propynyl)-3-pyrrolidinyl ester                            5,089,518                                                                 __________________________________________________________________________

EXAMPLE 318 (R)-Ethylcarbamic acid 1-[4-(dimethylamino)-2-butynyl-2-oxo-3-pyrrolidinyl ester

A solution of 2.2 g the product from Example 319, 0.93 g of dimethylamine, 0.8 g of paraformaldehyde, 1.85 g of acetic acid 0.050 g of cuprous chloride in 50 ml, of dioxane is heated at reflux temperature for 45 min. The mixture is cooled and concentrated at reduced pressure. The residue is basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, and concentrated at reduced pressure to dryness. The residue is purified (Alumina, Activity Grade 2.5: ethyl acetate/hexane 1:1 (v/v)) to give the product as in Example 138.

The following Examples 319-320, found in Table XXIII, are prepared by the procedures listed.

                                      TABLE XXIII                                  __________________________________________________________________________          Starting                                                                       Material      Procedure                                                   Example                                                                             Example       of                                                          No.  No.  Reagent  Example #                                                                            Name of Product                                       __________________________________________________________________________     319  313  2-(Methylamino)                                                                         88    (R)-Ethylcarbamic acid, 1-[4-[(2-                               ethanol        hydroxyethyl)methylamino]-2-butynyl]-                                          2-oxo-3-pyrrolidinyl ester                            320  313  4-(Methylamino)-                                                                        88    (R)-Ethylcarbamic acid, 1-[4-[(4-                               1-butanol      hydroxyethyl)methylamino]-2-butynyl]-                                          2-oxo-3-pyrrolidinyl ester                            __________________________________________________________________________ 

We claim:
 1. A compound of Formula I ##STR16## wherein R₁ and R₂ are, independently, (C₁ -C₆)alkyl or (C₃ -C₇)cycloalkyl;R₃ is (C₂ -C₁₀)alkanoyloxy, (C₃ -C₇)cycloalkylcarbonyloxy, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]carbonyloxy, aroyloxy, aryl(C₁ -C₄)alkylcarbonyloxy, (C₁ -C₁₀)alkoxycarbonyloxy, (C₃ -C₇)cyclo-alkoxycarbonyloxy, (C₃ -C₇)cycloalkyl[(C₁ -C₄)-alkoxy]carbonyloxy, aryloxycarbonyloxy, aryl(C₁ -C₄)alkyloxycarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy, (C₃ -C₇)cycloalkylaminocarbonyloxy, (C₃ -C₇)cycloalkyl[(C₁ -C₄)alkyl]aminocarbonyloxy, arylaminocarbonyloxy, aryl(C₁ -C₄)alkyl-aminocarbonyloxy, (C₁ -C₁₀)dialkylaminocarbonyloxy, aryl[(C₁ -C₄)alkyl]aminocarbonyloxy, (C₃ -C₇)cycloalkyl(C₁ -C₄)alkylaminocarbonyloxy, diarylaminocarbonyloxy, and bis[aryl(C₁ -C₄)alkyl]aminocarbonyloxy, in which any aryl group is phenyl, 2-naphthyl or 4-biphenyl, and R₄ is hydrogen or (C₁ -C₆)alkyl,or a pharmaceutically acceptable salt thereof.
 2. A compound of Formula I of claim 1 ##STR17## wherein R₁ and R₂ are, independently, (C₁ -C₆)alkyl;R₃ is (C₂ -C₁₀)alkanoyloxy, (C₁ -C₁₀)alkoxycarbonyloxy, (C₁ -C₁₀)alkylaminocarbonyloxy, and R₄ is hydrogen or (C₁ -C₃)alkyl,or a pharmaceutically acceptable salt thereof.
 3. A compound of claim 1 selected from the group consisting of(S)-octanoic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (S)-ethylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (S)-butylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (S)-hexylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (S)-octylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (S)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid ethyl ester; (S)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid butyl ester; (S)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid hexyl ester; (R)-octanoic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (R)-ethylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (R)-butylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (R)-hexylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester; (R)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid ethyl ester; (R)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid butyl ester; (R)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid hexyl ester;and a pharmaceutically acceptable salt of these compound esters.
 4. The compound according to claim 1 which is (S)-octanoic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 5. The compound according to claim 1 which is (S)-ethylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 6. A compound according to claim 1 which is (S)-butylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 7. A compound according to claim 1 which is (S)-hexylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 8. A compound according to claim 1 which is (S)-octylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 9. A compound according to claim 1 which is (S)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid ethyl ester or a pharmaceutically acceptable salt thereof.
 10. A compound according to claim 1 which is (S)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid butyl ester or a pharmaceutically acceptable salt thereof.
 11. A compound according to claim 1 which is (S)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid hexyl ester or a pharmaceutically acceptable salt thereof.
 12. A compound according to claim 1 which is (R)-octanoic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 13. A compound according to claim 1 which is (R)-ethylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 14. A compound according to claim 1 which is (R)-butylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 15. A compound according to claim 1, (R)-hexylcarbamic acid 1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl ester or a pharmaceutically acceptable salt thereof.
 16. A compound according to claim 1 (which is (R)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid ethyl ester or a pharmaceutically acceptable salt thereof.
 17. A compound according to claim 1 which is (R)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid butyl ester or a pharmaceutically acceptable salt thereof.
 18. A compound according to claim 1 which is (R)-1-[4-(dimethylamino)-2-butynyl]-2-oxo-3-pyrrolidinyl carbonic acid hexyl ester or a pharmaceutically acceptable salt thereof. 